Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk

We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.     

Mismatch negativity,social cognition,and functional outcomes in patients after traumatic brain injury

Mismatch negativity is generated automatically, and is an early monitoring indicator of neuronal integrity impairment and functional abnormality in patients with brain injury, leading to decline of cognitive function. Antipsychotic medication cannot affect mismatch negativity. The present study aimed to explore the relationships of mismatch negativity with neurocognition, daily life and social functional outcomes in patients after brain injury. Twelve patients with traumatic brain injury and 12 healthy controls were recruited in this study. We examined neurocognition with the Wechsler Adult Intelligence Scale-Revised China, and daily and social functional outcomes with the Activity of Daily Living Scale and Social Disability Screening Schedule, respectively. Mismatch negativity was analyzed from electroencephalogram recording. The results showed that mismatch negativity amplitudes decreased in patients with traumatic brain injury compared with healthy controls. Mismatch negativity amplitude was negatively correlated with measurements of neurocognition and positively correlated with functional outcomes in patients after traumatic brain injury. Further, the most significant positive correlations were found between mismatch negativity in the fronto-central region and measures of functional outcomes. The most significant positive correlations were also found between mismatch negativity at the FCz electrode and daily living function. Mismatch negativity amplitudes were extremely positively associated with Social Disability Screening Schedule scores at the Fz electrode in brain injury patients. These experimental findings suggest that mismatch negativity might efficiently reflect functional outcomes in patients after traumatic brain injury.     

Neuropsychological and neuroimaging findings in traumatic brain injury and post-traumatic stress disorder

Advances in imaging technology, coupled with military personnel returning home from Iraq and Afghanistan with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), have increased interest in the neuropsychology and neurobiology of these two conditions. There has been a particular focus on differential diagnosis. This paper provides an overviev of findings regarding the neuropsychological and neurobiological underpinnings of TBI and for PTSD. A specific focus is on assessment using neuropsychological measures and imaging techniques. Challenges associated with the assessment of individuals with one or both conditions are also discussed. Although use of neuropsychological and neuroimaging test results may assist with diagnosis and treatment planning, further work is needed to identify objective biomarkers for each condition. Such advances would be expected to facilitate differential diagnosis and implementation of best treatment practices.     

Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter?

The targeted brain dysfunction that accompanies aging can have a devastating effect on cognitive and intellectual abilities. A significant proportion of older adults experience precipitous cognitive decline that negatively impacts functional activities. Such individuals meet clinical diagnostic criteria for dementia, which is commonly attributed to Alzheimer''s disease (AD). Structural neuroimaging, including magnetic resonance imaging (MRI), has contributed significantly to our understanding of the morphological and pathology-related changes that may underlie normal and disease-associated cognitive change in aging. White matter hyperintensities (WMH), which are distributed patches of increased hyperintense signal on T2-weighted MRI, are among the most common structural neuroimaging findings in older adults. In recent years, WMH have emerged as robust radiological correlates of cognitive decline. Studies suggest that WMH distributed in anterior brain regions are related to decline in executive abilities that is typical of normal aging, whereas WMH distributed in more posterior brain regions are common in AD. Although epidemiological, observational, and pathological studies suggest that WMH may be ischemic in origin and caused by consistent or variable hypoperfusion, there is emerging evidence that they may also reflect vascular deposition of (β-amyloid, particularly when they are distributed in posterior areas and are present in patients with AD. Findings from the literature highlight the potential contribution of small-vessel cerebrovascular disease to the pathogenesis of AD, and suggest a mechanistic interaction, but future longitudinal studies using multiple imaging modalities are required to fully understand the complex role of WMH in AD.     

Neuroimaging correlates of cognitive and functional outcome after traumatic brain injury

Magnetic resonance imaging (MRI) may provide an estimate of the severity of diffuse axonal injury by quantitative measurements of atrophy of white matter tracts (such as corpus callosum) and of ventricular enlargement (particularly the third ventricle). However, most MRI studies failed to reveal consistent relationships between the pattern of neuropsychological impairments and the site and extent of focal structural lesions after traumatic brain injury. Functional neuroimaging techniques, such as positron emission tomography or functional MRI, may reveal areas of cerebral dysfunction in regions that look structurally intact on MRI. Studies using these techniques have suggested that the cognitive and behavioural disturbances of traumatic brain injury could be related to a defective activation of a prefrontal-cingulate network.     

Human intelligence and brain networks

Intelligence can be defined as a general mental ability for reasoning, problem solving, and learning. Because of its general nature, intelligence integrates cognitive functions such as perception, attention, memory, language, or planning. On the basis of this definition, intelligence can be reliably measured by standardized tests with obtained scores predicting several broad social outcomes such as educational achievement, job performance, health, and longevity. A detailed understanding of the brain mechanisms underlying this general mental ability could provide significant individual and societal benefits. Structural and functional neuroimaging studies have generally supported a frontoparietal network relevant for intelligence. This same network has also been found to underlie cognitive functions related to perception, short-term memory storage, and language. The distributed nature of this network and its involvement in a wide range of cognitive functions fits well with the integrative nature of intelligence. A new key phase of research is beginning to investigate how functional networks relate to structural networks, with emphasis on how distributed brain areas communicate with each other.     

Stability of rat models of fluid percussion-induced traumatic brain injury: comparison of three different impact forces

Fluid percussion-induced traumatic brain injury models have been widely used in experimental research for years. In an experiment, the stability of impaction is inevitably affected by factors such as the appearance of liquid spikes. Management of impact pressure is a crucial factor that determines the stability of these models, and direction of impact control is another basic element. To improve experimental stability, we calculated a pressure curve by generating repeated impacts using a fluid percussion device at different pendulum angles. A stereotactic frame was used to control the direction of impact. We produced stable and reproducible models, including mild, moderate, and severe traumatic brain injury, using the MODEL01-B device at pendulum angles of 6°, 11° and 13°, with corresponding impact force values of 1.0 ± 0.11 atm(101.32 ± 11.16 k Pa), 2.6 ± 0.16 atm(263.44 ± 16.21 k Pa), and 3.6 ± 0.16 atm(364.77 ± 16.21 k Pa), respectively. Behavioral tests, hematoxylin-eosin staining, and magnetic resonance imaging revealed that models for different degrees of injury were consistent with the clinical properties of mild, moderate, and severe craniocerebral injuries. Using this method, we established fluid percussion models for different degrees of injury and stabilized pathological features based on precise power and direction control.     

Introduction to the brain imaging and behavior special issue on neuroimaging findings in mild traumatic brain injury

Contemporary neuroimaging methods and research findings in mild traumatic brain injury (mTBI) are reviewed in this special issue. Topics covered include structural and functional neuroimaging techniques with a particular emphasis on the most contemporary research involving magnetic resonance imaging (MRI). Future research directions as well as applied applications of using neuroimaging techniques to define biomarkers of brain injury are covered.     

Concussion in athletics: ongoing clinical and brain imaging research controversies

Concussion, the most common form of traumatic brain injury, proves to be increasingly complex and not mild in nature as its synonymous term mild traumatic brain injury (mTBI) would imply. Despite the increasing occurrence and prevalence of mTBI there is no universally accepted definition and conventional brain imaging techniques lack the sensitivity to detect subtle changes it causes. Moreover, clinical management of sports induced mild traumatic brain injury has not changed much over the past decade. Advances in neuroimaging that include electroencephalography (EEG), functional magnetic resonance imaging (fMRI), resting-state functional connectivity, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) offer promise in aiding research into understanding the complexities and nuances of mTBI which may ultimately influence clinical management of the condition. In this paper the authors review the major findings from these advanced neuroimaging methods along with current controversy within this field of research. As mTBI is frequently associated with youth and sports injury this review focuses on sports-related mTBI in the younger population.     

Recent neuroimaging techniques in mild traumatic brain injury

Mild traumatic brain injury (TBI) is characterized by acute physiological changes that result in at least some acute cognitive difficulties and typically resolve by 3 months postinjury. Because the majority of mild TBI patients have normal structural magnetic resonance imaging (MRI)/computed tomography (CT) scans, there is increasing attention directed at finding objective physiological correlates of persistent cognitive and neuropsychiatric symptoms through experimental neuroimaging techniques. The authors review studies utilizing these techniques in patients with mild TBI; these techniques may provide more sensitive assessment of structural and functional abnormalities following mild TBI. Particular promise is evident with fMRI, PET, and SPECT scanning, as demonstrated by associations between brain activation and clinical outcomes.     

Neuroimaging Findings in Mild Traumatic Brain Injury *

The role of neuroimaging in the diagnosis and management of mild traumatic brain injury (TBI) is evolving. In general, the structural imaging techniques play a role in acute diagnosis and management, while the functional imaging techniques show promise for clarification of pathophysiology, symptom genesis, and mechanisms of recovery. A wide array of neuropathological processes are involved in mild TBI including changes in bone (e.g., a skull fracture), tissue density and water content (edema), blood flow, white matter integrity and pathway connectivity (diffuse axonal injury), and subtle changes in the neuronal and extracellular biochemical milieu. No single imaging technique is capable of addressing all these processes. It is, therefore, important to be aware of the advantages and limitations of the various available imaging modalities. This paper selectively reviews the pertinent literature on the structural and functional imaging in mild TBI.     

Neuroimaging findings in mild traumatic brain injury

The role of neuroimaging in the diagnosis and management of mild traumatic brain injury (TBI) is evolving. In general, the structural imaging techniques play a role in acute diagnosis and management, while the functional imaging techniques show promise for clarification of pathophysiology, symptom genesis, and mechanisms of recovery. A wide array of neuropathological processes are involved in mild TBI including changes in bone (e.g., a skull fracture), tissue density and water content (edema), blood flow, white matter integrity and pathway connectivity (diffuse axonal injury), and subtle changes in the neuronal and extracellular biochemical milieu. No single imaging technique is capable of addressing all these processes. It is, therefore, important to be aware of the advantages and limitations of the various available imaging modalities. This paper selectively reviews the pertinent literature on the structural and functional imaging in mild TBI.     

Cognitive neuroscience and brain imaging in bipolar disorder

Bipolar disorder is characterized by a combination of state-related changes in psychological function that are restricted to illness episodes, coupled with trait-related changes that persist through periods of remission, irrespective of symptom status. This article reviews studies that have investigated the brain systems involved in these state- and trait-related changes, using two techniques: (i) indirect measures of neurocognitive function, and (ii) direct neuroimaging measures of brain function during performance of a cognitive task. Studies of neurocognitive function in bipolar disorder indicate deficits in three core domains: attention, executive function, and emotional processing. Functional imaging studies implicate pathophysiology in distributed neural circuitry that includes the prefrontal and anterior cingulate cortices, as well as subcortical limbic structures including the amygdala and the ventral striatum. Whilst there have been clear advances in our understanding of brain changes in bipolar disorder, there are limited data in bipolar depression, and there is limited understanding of the influence of clinical variables including medication status, illness severity, and specific symptom dimensions.     

Resuscitation therapy for traumatic brain injuryinduced coma in rats:mechanisms of median nerve electrical stimulation

In this study, rats were put into traumatic brain injury-induced coma and treated with median nerve electrical stimulation. We explored the wake-promoting effect, and possible mechanisms, of median nerve electrical stimulation. Electrical stimulation upregulated the expression levels of orexin-A and its receptor OX1 R in the rat prefrontal cortex. Orexin-A expression gradually increased with increasing stimulation, while OX1 R expression reached a peak at 12 hours and then decreased. In addition, after the OX1 R antagonist, SB334867, was injected into the brain of rats after traumatic brain injury, fewer rats were restored to consciousness, and orexin-A and OXIR expression in the prefrontal cortex was downregulated. Our findings indicate that median nerve electrical stimulation induced an up-regulation of orexin-A and OX1 R expression in the prefrontal cortex of traumatic brain injury-induced coma rats, which may be a potential mechanism involved in the wake-promoting effects of median nerve electrical stimulation.     

Clinical applications of neuropsychological assessment

Neuropsychological assessment is a performance-based method to assess cognitive functioning. This method is used to examine the cognitive consequences of brain damage, brain disease, and severe mental illness. There are several specific uses of neuropsychological assessment, including collection of diagnostic information, differential diagnostic information, assessment of treatment response, and prediction of functional potential and functional recovery. We anticipate that clinical neuropsychological assessment will continue to be used, even in the face of advances in imaging technology, because it is already well known that the presence of significant brain changes can be associated with nearly normal cognitive functioning, while individuals with no lesions detectable on imaging can have substantial cognitive and functional limitations.     

Sensitivity and specificity of neuroimaging for the diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is one of the most devastating and cosily disorders affecting the aging population. Structural imaging (computed tomography [CT] and magnetic resonance imaging [MRI]) and functional imaging (single photon emission computed tomography [SPECT] and positron emission tomography [PET]) have been evaluated for their roles in the imaqinq diagnosis of AD. We have reviewed the recent literature to determine the capabilities of these neuroimaging techniques in comparison to current standards of clinical diagnosis. Our results indicate that there is wide variability in the accuracy of clinical assessments, in contrast to a more limited ranqe of variability of the accuracy of neuroimaqinq measurements. These results suggest that neuroimaging may serve an adjunctive role in raising this lower bound of diagnostic accuracy. Furthermore, we suggest that neuroimaging should be considered: (I) when clinical expertise is insufficient; (il) as a complement to specific likelihood ratios; and (iii) in specific types of patients, for whom clinical evaluation is inappropriate or inadequate.     

Strategies to avoid a missed diagnosis of co-occurring concussion in post-acute patients having a spinal cord injury

Research scientists and clinicians should be aware that missed diagnoses of mild-moderate traumatic brain injuries in post-acute patients having spinal cord injuries may approach 60–74% with certain risk factors, potentially causing clinical consequences for patients, and confounding the results of clinical research studies. Factors leading to a missed diagnosis may include acute trauma-related life-threatening issues, sedation/intubation, subtle neuropathology on neuroimaging, failure to collect Glasgow Coma Scale scores or duration of posttraumatic amnesia, or lack of validity of this information, and overlap in neuro-cognitive symptoms with emotional responses to spinal cord injuries. Strategies for avoiding a missed diagnosis of mild-moderate traumatic brain injuries in patients having a spinal cord injuries are highlighted in this perspective.     

Structure and function of complex brain networks

An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a “rich club,” centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed.     

Functional magnetic resonance imaging in schizophrenia

The integration of functional magnetic resonance imaging (fMRI) with cognitive and affective neuroscience paradigms enables examination of the brain systems underlying the behavioral deficits manifested in schizophrenia; there have been a remarkable increase in the number of studies that apply fMRI in neurobiological studies of this disease. This article summarizes features of fMRI methodology and highlights its application in neurobehavioral studies in schizophrenia. Such work has helped elucidate potential neural substrates of deficits in cognition and affect by providing measures of activation to neurobehavioral probes and connectivity among brain regions. Studies have demonstrated abnormalities at early stages of sensory processing that may influence downstream abnormalities in more complex evaluative processing. The methodology can help bridge integration with neuropharmacologic and genomic investigations.     

Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury

The Notch signaling pathway plays a key role in angiogenesis and endothelial cell formation, but it remains unclear whether it is involved in vascular repair by endothelial progenitor cells after traumatic brain injury. Therefore, in the present study, we controlled the Notch signaling pathway using overexpression and knockdown constructs. Activation of the Notch signaling pathway by Notch1 or Jagged1 overexpression enhanced the migration, invasiveness and angiogenic ability of endothelial progenitor cells. Suppression of the Notch signaling pathway with Notch1 or Jagged1 si RNAs reduced the migratory capacity, invasiveness and angiogenic ability of endothelial progenitor cells. Activation of the Notch signaling pathway in vivo in a rat model of mild traumatic brain injury promoted neurovascular repair. These findings suggest that the activation of the Notch signaling pathway promotes blood vessel formation and tissue repair after brain trauma.