Hippocampal shape alterations in healthy young women with familial risk for unipolar depression.

BACKGROUND: Although reduced hippocampal volume (HCV) is a common finding in depression, it is unclear whether the structural alterations leading to reduction of HCV are pre-existing risk factors before the onset of clinical symptoms or a cumulative process that begins with the onset of clinical symptoms. The aim of the present study was to understand the anatomical status of the hippocampus prior to the clinical symptoms in subjects with high familial risk for depression. METHODS: Twenty-seven young women (mean age: 22.3 ±â€¯2.1 years) who were at high risk for familial unipolar depression and 26 age- and gender-matched healthy controls (mean age: 22.1 ±â€¯2.1 years) with low familial risk for depression were included in the study. Total hippocampal volumes were measured by manual tracing. For 3D shape differences, the spherical harmonic basis functions (SPHARM) software was used. The segmented images were parameterized, and the point-to-point based group difference was compared by the Hotelling's T-squared test with total brain volume and Beck Depression Scale as covariates. RESULTS: Although there was no difference in overall HCVs, shape analyses revealed a contracted area on the Cornu Ammonis (CA) 1 region of the right hippocampus head in the high-risk group compared to the low-risk group. Cross-sectional design and small sample size, including only females, were the main limitations of this study. CONCLUSION: This study with shape analyses provided data suggesting that local structural hippocampal alterations in the CA1 region might be associated with depression vulnerability in women at high risk.

Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings.

Alzheimer's disease (AD) is commonly associated with noncognitive behavioral changes (NCBCs). The authors systematically reviewed whether neuroimaging has helped with understanding the pathophysiology, diagnosis, or management of NCBCs associated with AD, including depression, aggression or agitation, anxiety, apathy, psychosis, and sleep disorder. The authors identified dissociable neural substrates with multimodal imaging: depression implicates the lateral and superior prefrontal cortex; apathy and agitation implicate the dorsal anterior cingulate; psychosis implicates right lateralized frontal and medial temporal areas; and anxiety implicates mesial temporal regions. Frontal white matter changes appear to underlie many NCBCs, emphasizing the preventative management of vascular risk factors. Further delineation of underlying neurocircuitry and pathophysiology in larger data sets might lead to biomarker identification for diagnosis and optimizing treatment targets.

Cortisol response patterns in depressed women and their healthy daughters at risk: Comparison with healthy women and their daughters.

A dysfunctional hypothalamic pituitary adrenal (HPA) axis is widely accepted as a significant pathophysiological aspect of Major Depressive Disorder (MDD). Despite studies suggesting that a dysfunctional HPA axis might be present before the clinical syndrome becomes apparent, the functioning of the HPA axis in high-risk populations has not been well defined. The aim of the present study was to investigate the HPA axis functioning of mothers suffering from MDD and their healthy daughters compared to age- and sex-matched healthy controls. This design allowed a comparison of HPA axis functional differences among daughter and mother groups. HPA axis function was evaluated with a modified dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which was performed after obtaining the diurnal adrenocorticotropic hormone (ACTH) and cortisol values at 8:00, 16:00, and 23:00 h. We found that MDD mothers and their daughters had low morning cortisol and the MDD mothers additionally had low-morning ACTH compared with controls. Dexamethasone suppressed both cortisol and ACTH in all groups and subsequent HPA axis stimulation by CRH-evoked a lower cortisol response but a higher ACTH response among subjects with MDD mothers. Although high-risk daughters had comparable cortisol levels after CRH infusion, the AUC for ACTH was greater than those of controls. These patterns of results suggest that multiple level HPA dysfunctions are present in both MDD patients and their high-risk carrying daughters. However, insufficient cortisol secretion was only present in MDD mothers, while the daughters could compensate cortisol levels during CRH challenge.

P300 energy loss in aging and Alzheimer's disease.

The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer's disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an "oddball" task in 14 young normal individuals (YN: 21-41 years), 11 elderly normal individuals (EN: 61-80 years), and 23 probable AD patients (AD: 63-93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD.

Evaluation of traumatic brain injury: brain potentials in diagnosis, function, and prognosis.

The focus of this review is an analysis of the use of event-related brain potential (ERP) abnormalities as indices of functional pathophysiology in survivors of traumatic brain injury (TBI). TBI may be the most prevalent but least understood neurological disorder in both civilian and military populations. In the military, thousands of new brain injuries occur yearly; this lends considerable urgency to the use of highly sensitive ERP tools to illuminate brain changes and to address remediation issues. We review the processes thought to be indexed by the cognitive components of the ERP and outline the rationale for applying ERPs to evaluate deficits after TBI. Studies in which ERPs were used to clarify the nature of cognitive complaints of TBI survivors are reviewed, emphasizing impairment in attention, information processing, and cognitive control. Also highlighted is research on the application of ERPs to predict emergence from coma and eventual outcome. We describe primary blast injury, the leading cause of TBI for active duty military personnel in present day warfare. The review concludes with a description of an ongoing investigation of mild TBI, aimed at using indices of brain structure and function to predict the course of posttraumatic stress disorder. An additional goal of this ongoing investigation is to characterize the structural and functional sequelae of blast injury.

Psychopharmacological neuroprotection in neurodegenerative disease: heuristic clinical applications.

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research.

Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.

Rhythmic oscillations in quantitative EEG measured during a continuous performance task.

The objective of the present investigation was to determine if cyclic variations in human performance recorded during a 30 min continuous performance task would parallel cyclic variations in right-hemisphere beta-wave activity. A fast fourier transformation was performed on the quantitative electroencephalogram (qEEG) and the performance record of each participant (N = 62), producing an individual periodogram for each outcome measure. An average periodogram was then produced for both qEEG and performance by combining (averaging) the amplitudes associated with each periodicity in the 62 original periodograms. Periodicities ranging from 1.00 to 2.00 min and from 4.70 to 5.70 min with amplitudes greater than would be expected due to chance were retained (Smith et al. 2003). The results of the present investigation validate the existence of cyclic variations in human performance that have been identified previously (Smith et al. 2003) and extend those findings by implicating right-hemisphere mediated arousal in the process (Arruda et al. 1996, 1999, 2007). Significant cyclic variations in left-hemisphere beta-wave activity were not observed. Taken together, the findings of the present investigation support a model of sustained attention that predicts cyclic changes in human performance that are the result of cyclic changes in right-hemisphere arousal.

The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association.

This report reviews the state of the literature and opportunities for research related to the cognitive correlates of functional status. The prediction of functional capacity on the basis of cognitive test performance is an important aspect of neuropsychological assessment. Moreover, functional impairment or "disability" is an essential part of dementia case finding. Nevertheless, relatively little attention has been given to the empirical study of the specific cognitive correlates of functional outcomes. What literature is available suggests that 1) the variance in functional status that can be specifically attributed to cognition is surprisingly modest; 2) some cognitive domains may be more relevant to functional capacity than others; 3) some measures of executive control function are relatively strong correlates of functional capacities, particularly medical or financial decision-making; and 4) "general" cognitive screening tests are surprisingly strong correlates of functional status. These findings are of particular significance to dementia case finding, epidemiology, and treatment. The extensive literature on functional status has yet to be integrated with the equally extensive literature on cognitive assessment. Better integration of cognitive and functional assessments would offer greater clinical utility. However, psychometric batteries may have to be redesigned to maximize their capacity to capture the variance in functional outcomes.

Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA Committee on Research).

Psychiatric disorders frequently complicate recovery and rehabilitation from traumatic brain injury (TBI). This study reviews the literature from 1978 to 2006 on psychosis, depression, posttraumatic stress disorder, mania, and aggression following nonpenetrating TBI. The studies were reviewed using the American Academy of Neurology's criteria for classification of articles on diagnostic methods. No studies were found to be Class I or II. Of the 66 studies reviewed, the majority were Class IV. There are significant gaps in the literature on post-TBI psychiatric conditions with respect to nosology, epidemiology, and risk factors. Larger multicenter prospective studies using standardized diagnostic instruments are needed to further clarify the nosology, risk factors, and clinical course of these disorders. Specific directions for research are provided.

A quantitative electroencephalographic correlate of sustained attention processing.

The objective of the present investigation was to develop a quantitative electroencephalographic measure (qEEG) that is sensitive and specific to changes in sustained human performance. A principal components analysis (PCA) was performed on the qEEG obtained from participants during a continuous performance test. Measures of sensitivity (proportion of correctly identified correct responses, or hits) and specificity (proportion of correctly identified incorrect responses, or misses) were calculated to assess the classification accuracy of each newly derived component. PCA solutions produced a right hemisphere component comprised of beta-wave activity measured from four unipolar sites (F8, C6a, C6, and T4) that appeared to be sensitive and specific to changes in human performance. Results provide evidence for the validity of a right hemisphere qEEG measure that is sensitive and specific to changes in sustained human performance. Consistent with the findings of previous research, the present findings implicate the right cerebral hemisphere in the sustained attention process.

The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association.

The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG's applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG's cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.

Effects of flash mode and intensity on P2 component latency and amplitude.

UNLABELLED: Alzheimer's disease (AD) groups manifest flash visual-evoked potential (VEP) P2 component delays compared to healthy control groups. However, using P2 latency to categorize individual patients and controls yields low accuracy. Additionally, several laboratories have failed to replicate the basic between group P2 latency findings. The sporadic failure to find the P2 delay and, when found, its failure to classify patients and controls accurately may reflect the use of non-optimal stimuli or recording sites. OBJECTIVE: This was a parametric investigation of stimulation and recording methods in healthy college students. METHOD: Using an extended recording montage of 64 electrodes, 10 stimulus conditions (5 flash intensities through open and closed eyes) were evaluated for their P2 effects. RESULT: The optimal recording site (O2) yielded the most reliable latencies and amplitudes across a range of stimulus intensities. Flash intensity did not affect P2 latency or amplitude. Flashes delivered through closed eyelids produced a flash VEP but delivery through open eyes produced a pattern VEP lacking a flash P2 component. CONCLUSION: This accounts for the failure of some laboratories using open eyes to replicate the P2 delay in AD groups. SIGNIFICANCE: Optimal flash VEP conditions include closed eyes and recording from O2. Flash intensity is unimportant.

Diagnostic utility of visual evoked potential changes in Alzheimer's disease.

Previous studies have consistently found a selective delay of the P2 flash visual evoked potential (VEP) component among groups of patients with Alzheimer's dementia (AD) compared with control groups. Several authors have termed the selective P2 delay a "marker" for AD and have called for its use in clinical diagnosis. This study examined the diagnostic utility of the selective P2 delay in a retrospective sample of 45 AD patients and 60 age-equivalent healthy control subjects. Although significant between-group differences were found, classification accuracies for individual patients and controls were too low for the P2 delay to contribute meaningfully to clinical diagnosis.