Journal of Integrative Neuroscience

There is little consensus about which objective markers should be used to assess major psychiatric disorders, and predict/evaluate treatment response for these disorders. Clinical practice relies instead on subjective signs and symptoms, such that there is a "translational gap" between research findings and clinical practice. This gap arises from: a) a lack of integrative theoretical models which provide a basis for understanding links between gene-brain-behavior mechanisms and clinical entities; b) the reliance on studying one measure at a time so that linkages between markers are their specificity are not established; and c) the lack of a definitive understanding of what constitutes normative function. Here, we draw on a standardized methodology for acquiring multiple sources of genomic, brain and behavioral data in the same subjects, to propose candidate markers of selected psychiatric disorders: depression, post-traumatic stress disorder, schizophrenia, attention-deficit/hyperactivity disorder and dementia disorders. This methodology has been used to establish a standardized international database which provides a comprehensive framework and the basis for testing hypotheses derived from an integrative theoretical model of the brain. Using this normative base, we present preliminary findings for a number of disorders in relation to the proposed markers. Establishing these objective markers will be the first step towards determining their sensitivity, specificity and treatment prediction in individual patients.

Aims: To examine how general (e.g., memory, attention) and social (emotional and interpersonal processes) cognition relate to measures of brain function and structure.

Methods: PCA was used to identify general and social cognitive factors from the Brain Resource International Database in 1,316 subjects. The identified factors were correlated with each subject's corresponding brain structure (MRI) and function (EEG/ERP) data.

Results: Seven core cognitive factors were identified for general and three for social. General cognition was correlated with global grey matter, while social cognition was negatively correlated with grey matter in fronto-temporal-somatosensory regions. Executive function, information processing speed and verbal memory performance were correlated with delta-theta qEEG, while most general cognitive factors negatively correlated with beta qEEG. Faster information processing speed was correlated with alpha qEEG. Executive function and information processing speed was correlated with negative-going ERP amplitude and slower ERP latency at frontal sites, but at posterior sites negative correlations were found.

Discussion: In contrast to general cognition, social cognition is identified by different functional (automated) activity and more localized neural structures. Only general cognition, requiring more effortful, controlled processing is related to brain function measures, particularly in frontal cortices.

Integrative Significance: Recording measures from multiple modalities including MRI, EEG/ERP, social and general cognition within the same subject provides a method of brain profiling for use in cognitive-neurotherapy and pharmacological studies.

Aims: Following an integrative neuroscience perspective, we propose that cognitive and emotional functions are integrally linked, and that genetic polymorphisms which impact upon neural processes may have complementary effects on these functions. The brain-derived neurotrophic factor (BDNF) 66Met allele may contribute to both cognitive and emotional aspects of the depression phenotype.

Methods: In 374 nonclinical subjects, BDNF genotype differences in task-related ERPs, emotion, memory, and EEG cortical arousal were examined.

Results: Using path modeling, higher negative affect in Met homozygotes was predicted by slow-wave EEG via the mediating effects of neuroticism. Both negative affect and working memory deficits were predicted by disturbances in emotion- and cognitive-related ERPs. This model held across groups with varying levels of depressed mood.

Discussion: Since impairments in emotion and working memory are core features of major depression, the BDNF Met allele may contribute to vulnerability for this disorder. An integrative approach in which genotypes are considered in combination with brain function and behavioral measures may be important in identifying profile markers of depression.

Integrative Significance: This study directly demonstrates that cognitive and emotional neural networks are not parallel independent systems, but rather highly integrated with effects on both cognitive performance and emotional behavior.

Aims: To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery.

Methods: A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them.

Results: MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components.

Discussion: These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response.

Integrative Significance: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.

Aims: Increasing age is the strongest risk factor for Alzheimer's disease (AD). Yet, departure from normal age-related decline for established markers of AD including memory, cognitive decline and brain function deficits, has not been quantified.

Methods: We examined the cross-sectional estimates of the "rate of decline" in cognitive performance and psychophysiological measures of brain function over age in AD, preclinical (subjective memory complaint-SMC, Mild Cognitive Impairment-MCI) and healthy groups. Correlations between memory performance and indices of brain function were also conducted.

Results: The rate of cognitive decline increased between groups: AD showed advanced decline, and SMC/MCI groups represented intermediate stages of decline relative to normal aging expectations. In AD, advanced EEG alterations (excessive slow-wave/reduced fast-wave EEG, decreased working memory P450 component) were observed over age, which were coupled with memory decline. By contrast, MCI group showed less severe cognitive changes but specific decreases in the working memory N300 component and slow-wave (delta) EEG, associated with decline in memory.

Discussion and Integrative Significance: While the cognitive data suggests a continuum of deterioration associated with increasing symptom severity across groups, integration with brain function measures points to possible distinct compensatory strategies in MCI and AD groups. An integrative approach offers the potential for objective markers of the critical turning point, with age as a potential factor, from mild memory problems to disease.

Aims: QEEG and neuropsychological tests were used to investigate the underlying neural processes in dyslexia.

Methods: A group of dyslexic children were compared with a matched control group from the Brain Resource International Database on measures of cognition and brain function (EEG and coherence).

Results: The dyslexic group showed increased slow activity (Delta and Theta) in the frontal and right temporal regions of the brain. Beta-1 was specifically increased at F7. EEG coherence was increased in the frontal, central and temporal regions for all frequency bands. There was a symmetric increase in coherence for the lower frequency bands (Delta and Theta) and a specific right-temporocentral increase in coherence for the higher frequency bands (Alpha and Beta). Significant correlations were observed between subtests such as Rapid Naming Letters, Articulation, Spelling and Phoneme Deletion and EEG coherence profiles.

Discussion: The results support the double-deficit theory of dyslexia and demonstrate that the differences between the dyslexia and control group might reflect compensatory mechanisms.

Integrative Significance: These findings point to a potential compensatory mechanism of brain function in dyslexia and helps to separate real dysfunction in dyslexia from acquired compensatory mechanisms.

Aims: The purpose of the present case is to describe the functional outcome of a patient with human immunodeficiency virus (HIV) and progressive multifocal leukoencephalopathy (PML) on treatment with antiretroviral therapy using a multidisciplinary approach.

Methods: Neuropsychological tests and diffusion tensor imaging (DTI) were obtained at baseline and after 12 months to define the severity of white matter damage. Neuropsychological and neuroimaging data were compared to an HIV-infected patient without PML and with good immune system health, and to a second HIV-infected patient without PML but with notable immunosuppression.

Results: Review of the HIV/PML patient's cognitive data at both time points revealed significant impairments compared to the control subjects. Similarly, the HIV/PML patient's white matter lesion load and whole brain volume were markedly different from the control subjects at both time points. The tractography-defined metrics suggest significant white matter fiber loss associated with HIV/PML that was not evident in either HIV control patient.

Discussion: Our findings suggest that PML is associated with marked cognitive and neuroimaging abnormalities in the context of antiretroviral therapy.

Integrative Significance: To our knowledge this is the first study to integrate both quantitative DTI and cognitive assessment to define white matter damage associated with HIV and PML. This integrative approach provides a robust methodology to examine the integrity of brain systems mediating cognitive function.

Aims: This study investigated the relationship between electroencephalograph (EEG) power and basal metabolic rate (BMR) over the human lifespan, to better understand the mechanisms involved in the decline of neural activity with age.

Methods: Eyes-open EEG power was calculated in standard frequency bands and averaged across recording sites in 1831 healthy subjects aged 6 to 86 years, from the Brain Resource International Database. In a subset of 175 subjects, structural MRI scans were also undertaken to determine the role of grey matter. Cerebral metabolic rate (CMR) was estimated using two models of EEG power, based on: (1) normalization of BMR by total body mass, and (2) scaling by cortical grey matter.

Results: Regression analysis revealed a linear relationship between the CMR estimates and EEG power under both models. In the full sample, CMR explained 65% of the variance in delta power, and 53% of the variance in theta power over the age span.

Discussion: The results demonstrate that the large EEG signals in early childhood are associated with a higher BMR during that age.

Integrative Significance: The use of cross-modal measurements in this study highlights the utility of capturing data in an integrative framework to reveal fundamental physiological relationships.