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1.  Post-mortem Locus Coeruleus Neuron Count in Three American Veterans with Probable or Possible War-Related PTSD 
Because enhanced CNS noradrenergic postsynaptic responsiveness has been previously shown to contribute to PTSD pathophysiology, we investigated whether war-related posttraumatic stress disorder (WR-PTSD) is associated with a post-mortem change in neuronal counts in the locus coeruleus (LC).
Using post-mortem neuromorphometry, we counted the number of neurons in the right LC in seven deceased elderly male veterans. We classified three veterans as cases of probable or possible WR-PTSD.
All three veterans with probable or possible WR-PTSD were found to have substantially lower LC neuronal counts compared to four controls (three non-psychiatric veterans and one veteran with alcohol dependence and delirium tremens).
To our knowledge, this case series is the first report of LC neuronal counts in patients with PTSD or any other DSM-IV-TR anxiety disorder. Previous post-mortem brain tissue studies of Alzheimer’s Disease (AD) demonstrated an upregulation of NE biosynthetic capacity in surviving LC neurons. The finding reported here is consistent with the similar upregulation of NE biosynthetic capacity of surviving LC neurons in veterans who developed WR-PTSD. If replicated, the finding we report here in WR-PTSD may provide further explanation of the demonstrated effectiveness of PTSD treatment with propranolol and prazosin. Larger neuromorphometric studies of the LC in veterans with WR-PTSD and in other stress-induced and fear-circuitry disorders are warranted.
PMCID: PMC4484762  PMID: 16387990
Veterans; War; Fear-circuitry; Locus Coeruleus; Neuropathology
2.  A Psychological and Neuroanatomical Model of Obsessive-Compulsive Disorder 
Imaging, surgical, and lesion studies suggest that the prefrontal cortex (orbitofrontal and anterior cingulate cortexes), basal ganglia, and thalamus are involved in the pathogenesis of obsessive-compulsive disorder (OCD). On the basis of these findings several models of OCD have been developed, but have had difficulty fully integrating the psychological and neuroanatomical findings of OCD. Recent research in the field of cognitive neuroscience on the normal function of these brain areas demonstrates the role of the orbitofrontal cortex in reward, the anterior cingulate cortex in error detection, the basal ganglia in affecting the threshold for activation of motor and behavioral programs, and the prefrontal cortex in storing memories of behavioral sequences (called “structured event complexes” or SECs). The authors propose that the initiation of these SECs can be accompanied by anxiety that is relieved with completion of the SEC, and that a deficit in this process could be responsible for many of the symptoms of OCD. Specifically, the anxiety can form the basis of an obsession, and a compulsion can be an attempt to receive relief from the anxiety by repeating parts of, or an entire, SEC. The authors discuss empiric support for, and specific experimental predictions of, this model. The authors believe that this model explains the specific symptoms, and integrates the psychology and neuroanatomy of OCD better than previous models.
PMCID: PMC4476073  PMID: 19196924
3.  Asymmetric insular function predicts positional blood pressure in non-demented elderly 
40% of non-demented octogenarians have Braak stages consistent with insular involvement, and may be at risk for “age–related” autonomic dysfunction. We examined the association between insular resting Cerebral Blood Flow (rCBF) and cardiovascular functions in 29 non-demented elderly subjects who were highly screened to exclude comorbid cardiovascular disease. Mean insular rCBF was significantly higher on the right (R) than left (L). However, 35.4% of subjects had L dominant rCBF = a "HIGH” risk group. R insular rCBF was significantly lower in the HIGH risk group. This subset had significantly increased positional drops in systolic blood pressure. While these data cannot address AD as the specific cause, this possibility is being investigated in other cohorts.
PMCID: PMC4459127  PMID: 19622688
autonomic function; asymmetry; aging; Alzheimer’s disease; insula; orthostasis
4.  The Relationship between Telephone-Administered Cognitive-Behavioral Therapy for Depression and Neuropsychological Functioning in Parkinson’s disease 
This letter is the first to describe the impact of telephone-based Cognitive-Behavioral Therapy (CBT) for depression on neuropsychological functioning in Parkinson’s disease. Telephone-administered CBT was associated with improvements in verbal memory following 10 weeks of treatment. Baseline verbal and working memory were related to depression improvement over time.
PMCID: PMC4012558  PMID: 24763770
Parkinson’s disease; depression; cognition; psychosocial intervention
5.  Independence of Changes in Behavior From Cognition and Function in Community-Dwelling Persons With Alzheimer's Disease: A Factor Analytic Approach 
The authors’ main objective was to investigate the relationship between changes in psychopathological, cognitive and activity of daily living (ADL) instrument scores over 12 months in community-dwelling persons with Alzheimer's disease (AD). A secondary objective was to evaluate the validity of dividing the Clinical Dementia Rating (CDR), a global dementia staging instrument into cognitive and functional subscores.
Changes in measures of psychopathology, cognition and function between the baseline and 12-month visits were entered into these post hoc analyses of data from a one-year clinical trial to evaluate behavioral, cognitive and functional assessment instruments for use in clinical trials with AD patients. Exploratory factor analysis was used to determine whether there was independence between changes in any of these three domains of interest for this disease population; participants were a cohort of 187 well-characterized, community-dwelling persons with AD.
One-year change in the behavioral symptoms of this cohort of persons with AD was statistically independent from changes in scores on cognitive and functional measures. Some evidence of independence of 12 month changes in cognitive and functional measures was found. Cognitive and functional subscores for the CDR were supported. These findings suggest that changes in behavior and cognition in dementia may have distinct pathophysiologies.
PMCID: PMC4377284  PMID: 15746483
6.  Investigating Emergent Symptomatology as an Outcome Measure in a Behavioral Study of Alzheimer’s Disease 
These retrospective analyses represent a pilot study of a potential new outcome, expected emergence. The Behavior Rating Scale for Dementia (BRSD) was administered at the baseline and 12-month visits of a multicenter study. The authors computed the rates at which each BRSD symptom emerged over 12 months in normal elderly control subjects (n = 64). These normal rates were then applied as the expected emergent rate (EER) to a population of individuals with Alzheimer’s disease (n = 235). The comparison of expected emergence to observed emergence in Alzheimer’s disease showed interpretable differences. EER assesses whether treatments limit emergence in the target, relative to the standard, population. The ratio of expected to observed emergence provides an intuitively appealing quantification of treatment efficacy and can be used with any instrument that uses categorical or frequency ratings.
PMCID: PMC4371727  PMID: 12154155
7.  Apathy is associated with lower inferior temporal cortical thickness in mild cognitive impairment and normal elderly 
Apathy is a common neuropsychiatric symptom in Alzheimer’s disease (AD) dementia and amnestic mild cognitive impairment (MCI) and is associated with cortical atrophy in AD dementia. This study investigated possible correlations between apathy and cortical atrophy in 47 individuals with MCI and 19 clinically normal elderly (CN). Backward elimination multivariate linear regression was used to evaluate the cross-sectional relationship between scores on the Apathy Evaluation Scale and thickness of several cortical regions and covariates. Lower inferior temporal cortical thickness was predictive of greater apathy. Greater anterior cingulate cortical thickness was also predictive of greater apathy, suggesting an underlying reactive process.
PMCID: PMC4342844  PMID: 25716491
mild cognitive impairment; apathy; Alzheimer’s disease; magnetic resonance imaging; cortical atrophy
8.  Who Qualifies for Deep Brain Stimulation for OCD? Data from a Naturalistic Clinical Sample 
A few patients with obsessive-compulsive disorder (OCD) remain severely impaired despite exhausting best-practice treatments. For them, neurosurgery (stereotactic ablation or deep brain stimulation) might be considered. We investigated the proportion of treatment-seeking OCD patients, in a naturalistic clinical sample, who met contemporary neurosurgery selection criteria. Using comprehensive baseline data on diagnosis, severity, and treatment history for adult patients from the NIMH-supported Brown Longitudinal OCD Study, only two of 325 patients met screening criteria for neurosurgery. This finding prompts consideration of new models for clinical trials with limited samples as well as methods of refining entry criteria for such invasive treatments.
PMCID: PMC4093791  PMID: 24515679
Obsessive-compulsive disorder; Deep brain stimulation; Neurosurgery; Humanitarian device exemption
9.  Neuropsychological Outcomes Following Psychosocial Intervention for Depression in Parkinson’s disease 
The purpose of this paper is to describe neuropsychological outcomes in people with Parkinson’s disease (PD) following their participation in an NIH-sponsored, randomized-controlled trial of cognitive-behavioral treatment for depression. Improvements in mood were associated with modest gains in verbal memory and executive functioning, over the 10-week treatment period, and accounted for greater variance in neuropsychological outcomes at the end-of-treatment, than other known correlates of cognitive functioning in PD, such as disease severity, age, and education. Baseline working memory and executive skills were also associated with depression improvement over time.
PMCID: PMC4144827  PMID: 24275895
Parkinson’s disease; depression; cognition; psychosocial intervention
10.  Preliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain Development 
Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse (CSA), and 17 healthy women (18–22 years) were analyzed for sensitive periods effects on hippocampal and amydgala volume, frontal cortex gray matter volume and corpus callosum area. Hipppocampal volume was reduced in association with CSA at 3–5 years (β=−0.69, p<0.0001) and 11–13 years (β=−0.25, p<0.05). Corpus callosum was reduced with CSA at 9–10 years (β=−0.44, p<0.005), and frontal cortex was attenuated in subjects with CSA at ages 14–16 (β=−0.48, p<0.005). Brain regions have unique windows of vulnerability to the effects of traumatic stress.
PMCID: PMC4270804  PMID: 18806232
hippocampus; frontal cortex; corpus callosum childhood sexual abuse; stress; maltreatment; adolescents
11.  Associations of Sleep Disturbance Symptoms with Health-Related Quality of Life in Parkinson’s Disease 
We examined associations of different sleep disturbance symptoms with health-related quality of life (HRQOL) in 153 adults with Parkinson’s disease (PD). PD patients reported more snoring, sleep inadequacy, daytime somnolence, and sleep maintenance problems than the general population (p<0.001). Symptoms having the broadest and strongest unique associations with generic HRQOL (8 scales; 2 composites of SF-36) were daytime somnolence (5 scales; 1 composite), sleep initiation (8 scales; 2 composites), and awakening short of breath or with headache (6 scales; 2 composites) (p’s<0.05). Associations of selected sleep disturbance symptoms – some unanticipated – suggest that assessing specific symptoms is worthwhile in clinical care.
PMCID: PMC3960993  PMID: 24247858
sleep disturbance; Parkinson’s disease; health-related quality of life
12.  Disorganized Symptoms and Executive Functioning Predict Impaired Social Functioning in Subjects at Risk for Psychosis 
Predictors of social functioning deficits were assessed in 22 individuals “at risk” for psychosis. Disorganized symptoms and executive functioning predicted social functioning at follow-up. Early intervention efforts that focus on social and cognitive skills are indicated in this vulnerable population.
PMCID: PMC4113423  PMID: 22231319
Prodromal; At-Risk; Schizophrenia; Clinical; Social Functioning; Neurocognition
15.  Non-Clinical Obsessive Compulsive Symptoms and Executive Functions in Schizophrenia 
The impact of non-clinical obsessive compulsive symptoms (OCS) on neuropsychological functioning in schizophrenia has received little investigation. We evaluated whether severity and subtype of OCS are associated with executive functioning in schizophrenia. Twenty-nine patients with schizophrenia and 32 healthy subjects completed questionnaire and performance-based measures of executive functioning Overall OCS severity in patients was associated with poorer monitoring and cognitive flexibility per a questionnaire. Obsessing, hoarding, and checking were related to poorer executive functioning in daily life. Performance-based scores showed few correlations with OCS. Findings indicate that severity of non-clinical OCS subtypes contribute to the heterogeneity of executive functions in schizophrenia.
PMCID: PMC4075772  PMID: 20686137
Schizophrenia; OCD; Executive Function; Neuropsychology
16.  Dopaminergic Challenge With Bromocriptine One Month After Mild Traumatic Brain Injury: Altered Working Memory and BOLD Response 
Catecholamines, particularly dopamine, modulate working memory (WM). Altered sensitivity to dopamine might play a role in WM changes observed after traumatic brain injury (TBI). Thirty-one healthy controls (HC) and 26 individuals with mild TBI (MTBI) 1 month after injury were challenged with bromocriptine versus placebo before administration of a verbal WM functional MRI task. Bromocriptine was associated with improved WM performance in the HC but not the MTBI group. On bromocriptine, the MTBI group showed increased activation outside of a task-specific region of interest. Findings are consistent with the hypothesis that individuals with MTBI have altered responsivity to dopamine.
PMCID: PMC4074527  PMID: 21948888
17.  Apathy is associated with increased amyloid burden in mild cognitive impairment 
Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. We sought to determine whether apathy is associated with cortical amyloid burden measured by Pittsburgh Compound B (PiB) positron emission tomography (PET) and regional hypometabolism measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. We found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age (prs=−0.46, p=0.03), but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.
PMCID: PMC3957217  PMID: 24247857
Alzheimer’s disease; amyloid; apathy; 18F-flourodeoxyglucose; mild cognitive impairment; Pittsburgh Compound B; positron emission tomography
18.  Are Selective Serotonin Reuptake Inhibitors Associated With Greater Apathy in Parkinson’s Disease? 
Apathy is a common neuropsychiatric feature of Parkinson’s disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinson’s patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD.
PMCID: PMC3759813  PMID: 23037646
19.  Elevated Neurobehavioral Symptoms are Associated with Everyday Functioning Problems in Chronic Methamphetamine Users 
Chronic methamphetamine (MA) use is commonly associated with neural injury and neurocognitive deficits. We examined the nature and correlates of self-reported neurobehavioral symptoms (i.e., apathy, disinihibition, and executive dysfunction) in 73 individuals with histories of MA dependence (MA+) and 85 comparison participants with comparable demographics and risk histories. MA+ individuals endorsed significantly more severe neurobehavioral symptoms on the Frontal Systems Behavioral Scale (FrSBe), especially disinhibition and executive dysfunction. Elevations in neurobehavioral symptoms were independent of common comorbidities, including hepatitis C infection, Attention-Deficit/Hyperactivity Disorder, mood disorders, and other substance use factors. Notably, the severity of neurobehavioral symptoms were uniquely associated with self-reported decrements in instrumental activities of daily living in the MA dependent sample. Findings indicate that chronic MA users may experience elevated neurobehavioral symptoms of disinhibition and executive dysfunction, potentially increasing their risk of functional declines.
PMCID: PMC3735421  PMID: 23037647
Methamphetamine; Substance abuse; Executive dysfunction; Behavioral disinhibition; Neuropsychological assessment; Activities of daily living
20.  Subgenual Cingulate Theta Activity Predicts Treatment Response of Repetitive Transcranial Magnetic Stimulation in Participants With Vascular Depression 
Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression. Increased metabolism in the anterior cingulate cortex (ACC) is a known predictor for antidepressant response. The authors assessed whether increased theta power within the ACC predicts rTMS response in participants with vascular depression. Sixty-five participants were randomized to active or sham rTMS. Outcome was assessed using the Hamilton Depression Rating Scale. Electroencephalography was obtained, and comparisons were made among each group with a normative database using low-resolution electromagnetic tomography. Results suggest that vascular depression participants respond well to rTMS and that increased low-theta power in the subgenual ACC predicts response to rTMS.
PMCID: PMC3688059  PMID: 20160213
21.  [No title available] 
PMCID: PMC3647459  PMID: 21037120
22.  [No title available] 
PMCID: PMC3641646  PMID: 21304142
23.  [No title available] 
PMCID: PMC3640485  PMID: 23487198
24.  [No title available] 
PMCID: PMC3641161  PMID: 20160209
25.  Differential Effects of Executive Functioning on Suicide Attempts 
Suicide is common among individuals with psychiatric illness; executive functioning may be associated with suicide risk. The authors examined demographic, clinical, and executive-functioning variables in suicide ideators and suicide attempters, hypothesizing that attempters would demonstrate poorer executive-functioning skills. Seventy-seven participants with psychiatric illness completed a neuropsychological battery while hospitalized or residing in crisis-houses after expressing suicidal ideation (N=40) or making a suicide attempt (N=37). Logistic regression predicted suicide Ideator versus suicide Attempter status; suicide Attempters exhibited poorer inhibition but better problem-solving ability than suicide Ideators. Suicide attempt risk may be associated with better problem-solving skills, but worse inhibitory control.
PMCID: PMC3626287  PMID: 21677246

Results 1-25 (76)