Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Dust mite induces multiple polar T cell axes in human skin.

BACKGROUND: House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new-onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model AD's emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown. OBJECTIVE: To assess whether HDM APT reproduces AD. METHODS: Positive HDM APTs (n = 15) from patients with and without AD were evaluated, using genomic and immunohistochemistry studies, against intrapersonal control skin. RESULTS: APT lesions showed higher T cell and dendritic cell infiltrates vs. CONTROLS: Seven hundred and forty-three up- and 326 downregulated genes were differentially expressed in HDM APT (fold change >2 and false discovery rate < 0.05), with increased expression of Th2, Th9, Th17/Th22 polar cytokines (i.e. IL-5, IL-13, IL-9, IL-17, IL-22). CONCLUSION: While HDM caused significant Th2 skewing, it also illustrated differences in Th2 induction and barrier defects; thus, HDM APT does not fully simulate AD. Given its widespread availability and sensitization rates, HDM may potentially be a useful tool that represents select aspects of AD, psoriasis, or contact dermatitis.

Elevated triglycerides are associated with decreased executive function among adolescents with bipolar disorder.

OBJECTIVE: Cardiovascular risk factors that comprise metabolic syndrome (MetS) have been linked with cognition in adults with bipolar disorder (BD). This study examines the association between MetS components and executive function in adolescents with BD. METHODS: A total of 34 adolescents with BD and 35 healthy control (HC) adolescents were enrolled. MetS components included triglycerides, high-density lipoprotein, glucose, waist circumference, and systolic and diastolic blood pressure. Executive functioning was measured using the intra-extra-dimensional (IED) set-shifting task from the Cambridge Neuropsychological Tests Automated Battery. RESULTS: Adolescents with BD were more likely to have ≥1 MetS components (64.7%) as compared to HC participants (22.9%, χ(2) = 12.29, P = <0.001). Adolescents with BD also had poorer IED task performance compared to HC adolescents (composite Z-score: 0.21 ± 0.52 vs. 0.49 ± 0.51, P = 0.011). Within the BD group, IED composite Z-scores were correlated with diastolic blood pressure and triglyceride levels (ρ = -0.358, P = 0.041 and ρ = -0.396, P = 0.020 respectively). The association of triglycerides with executive function remained significant after controlling for age, IQ, and current use of second-generation antipsychotics. CONCLUSION: Elevated triglycerides are associated with poorer executive function among adolescents with BD. Studies of behavioural and pharmacological interventions targeting MetS components for the purpose of improving executive function among adolescents with BD are warranted.

The influence of comorbid disorders on the episodicity of bipolar disorder in youth.

OBJECTIVE: Bipolar disorder (BP) frequently co-occurs with other psychiatric disorders. We examine whether course of anxiety disorders (ANX), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), and substance use disorders (SUD) influence likelihood of recovery and recurrence of depression and mania in BP youth. METHOD: Weekly ratings of psychiatric disorder intensity were obtained from 413 participants of the Course and Outcome of BP Youth project, followed for an average of 7.75 years. Multiple-event Cox proportional hazards regression analyses examined worsening of comorbid disorders as predictors of mood episode recovery and recurrence. RESULTS: Increased severity in ANX and SUD predicted longer time to recovery and less time to next depressive episode, and less time to next manic episode. Multivariate models with ANX and SUD found that significant effects of ANX remained, but SUD only predicted longer time to depression recovery. Increased severity of ADHD and DBD predicted shorter time to recurrence for depressive and manic episodes. CONCLUSION: There are significant time-varying relationships between the course of comorbid disorders and episodicity of depression and mania in BP youth. Worsening of comorbid conditions may present as a precursor to mood episode recurrence or warn of mood episode protraction.

Impaired probabilistic reversal learning in youths with mood and anxiety disorders.

BACKGROUND: From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD: We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS: Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS: Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Cerebral [18 F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter-white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects.

Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder.

BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit hyperactivity disorder (ADHD) have been limited by small samples or measurement of single brain regions. Since the neuropsychological deficits in ADHD implicate a network linking basal ganglia and frontal regions, 12 subcortical and cortical regions and their symmetries were measured to determine if these structures best distinguished ADHD. METHODS: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were .82 or greater for all MRI measures. RESULTS: Subjects with ADHD had a 4.7% smaller total cerebral volume (P = .02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right > left asymmetry in the caudate (P = .006), smaller right globus pallidus (P = .005), smaller right anterior frontal region (P = .02), smaller cerebellum (P = .05), and reversal of normal lateral ventricular asymmetry (P = .03) in the ADHD group. The normal age-related decrease in caudate volume was not seen, and increases in lateral ventricular volumes were significantly diminished in ADHD. CONCLUSION: This first comprehensive morphometric analysis is consistent with hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD.

Sydenham's chorea: magnetic resonance imaging of the basal ganglia.

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenham's chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenham's chorea group. In contrast, neither total cerebral, prefrontal, or midfrontal volumes or thalamic area were increased. These results indicate the selective involvement of the basal ganglia in Sydenham's chorea.

Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the relation between specific frontostriatal structures (prefrontal cortex and basal ganglia) and response inhibition deficits observed in attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD and age-matched normal controls were scanned using magnetic resonance imaging (MRI) and tested on three response inhibition tasks. Behavioral performance was correlated with MRI-based anatomical measures of frontostriatal circuitry (prefrontal cortex and basal ganglia) implicated in ADHD. RESULTS: First, significant differences in performance by children with ADHD and normal volunteers were observed on all three response inhibition tasks. Second, performance on these tasks correlated only with those anatomical measures of frontostriatal circuitry observed to be abnormal in children with ADHD (e.g., the region of the prefrontal cortex, caudate, and globus pallidus, but not the putamen) in the authors' previous study. Third, significant correlations between task performance and anatomical measures of the prefrontal cortex and caudate nuclei were predominantly in the right hemisphere, supporting a role of right frontostriatal circuitry in response inhibition and ADHD. CONCLUSION: The data suggest a role of the right prefrontal cortex in suppressing responses to salient, but otherwise irrelevant events while the basal ganglia appear to be involved in executing these behavioral responses.

Functional brain imaging in neuropsychiatric disorders of childhood.

This review article presents a summary of the current state-of-the-art of functional brain imaging, with a primary focus on childhood neuropsychiatric disorders. Coverage is emphasized for developments that appear to be of current or potential future importance for the child neurologist and related pediatric specialist, and also from the perspective of the developmental neuroscientist. Emphasis is placed on the modalities of single photon emission computed tomography (SPECT), positron emission tomography (PET), and both "conventional" and "functional" magnetic resonance imaging, (MRI) including reference to the major new radiopharmaceutical and magnetic resonance-based imaging agents and techniques. The fundamental physicochemical processes underlying such studies are outlined, with citation of sources of more detailed information for the interested reader. A variety of imaging studies are reviewed for selected groups of childhood neuropsychiatric disorders, designed to illustrate the achievements and future promise of these imaging modalities. Areas of concentration are suggested for future imaging research in the field of childhood behavioral disorders, where these methods seem critical to improved understanding of pathogenetic mechanisms, as well as development of more effective treatment strategies.

Physical therapy care for low back pain. Monitored program of first-contact nonphysician care.

We studied the process and outcomes of physical therapist management of 107 patients with low back pain at a walk-in clinic. Sixty-seven patients with low back pain concurrently were assigned randomly to internists at the clinic. Physicians and physical therapists recorded baseline clinical data and management plans on standard check lists. Physical therapists used a validated algorithm that directed diagnostic evaluations and physician consultations, but all other physical therapist treatment decisions were unconstrained. Patients in the physical therapist and physician groups did not differ significantly. Physical therapists referred more patients to the physical therapy department than did physicians but recommended muscle relaxants, prescription analgesics, and bed rest less frequently. The occurrence of new symptoms, duration of symptoms, and duration of activity limitations were similar between the physician and physical therapy patient groups at a one-month follow-up examination. Physical therapist-managed patients expressed greater satisfaction than physician-managed patients with several aspects of their care. The percentage of functional improvement for highly dysfunctional patients was significantly greater for the physical therapist-managed patients than for the physician-managed patients. The implications of a physical therapist first-contact care program for health service organizations, health care policy, physical therapist training, and credentialing are discussed.

Changing the health care system: a professional education program for Hispanic leaders in California.

This article reports characteristics and evaluation findings on a program aimed at promoting change in California's health care system by training minority managers and policy specialists. Between 1990 and 1992, 30 Hispanic college graduates enrolled in the University of Southern California's Hispanic Leadership Program. Funded in part by the W. K. Kellogg Foundation, this program led to award of the Master of Health Administration degree and involved students in a series of community workshops. Evaluation took place via alumni surveys and focus groups. Although four individuals failed to complete the program, nearly all others entered careers potentially leading to positions of influence in health care delivery. Graduates indicated that they possessed most of the skills they considered necessary to help improve services to Hispanic people. All had taken concrete action toward this objective. Experience with the program has provided lessons valuable for conducting efforts of this kind, the principal one being that success requires substantial human and material resources. Long-term follow-up will be necessary to assess the program's ultimate impact on California's health care system.

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury.

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [(18)F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [(18)F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [(18)F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [(18)F]-T807 PET imaging revealed striatal and nigral [(18)F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [(18)F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [(18)F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [(18)F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [(18)F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [(18)F]-fluorodeoxyglucose, [(18)F]-Florbetapir and/or [(18)F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.

Dendritic spine changes associated with normal aging.

Given the rapid rate of population aging and the increased incidence of cognitive decline and neurodegenerative diseases with advanced age, it is important to ascertain the determinants that result in cognitive impairment. It is also important to note that much of the aged population exhibit 'successful' cognitive aging, in which cognitive impairment is minimal. One main goal of normal aging studies is to distinguish the neural changes that occur in unsuccessful (functionally impaired) subjects from those of successful (functionally unimpaired) subjects. In this review, we present some of the structural adaptations that neurons and spines undergo throughout normal aging and discuss their likely contributions to electrophysiological properties and cognition. Structural changes of neurons and dendritic spines during aging, and the functional consequences of such changes, remain poorly understood. Elucidating the structural and functional synaptic age-related changes that lead to cognitive impairment may lead to the development of drug treatments that can restore or protect neural circuits and mediate cognition and successful aging.