An 'integrative neuroscience' perspective on ADHD: linking cognition, emotion, brain and genetic measures with implications for clinical support.

There remains a translational gap between research findings and their implementation in clinical practice that applies to attention-deficit/hyperactivity disorder (ADHD), as well as to other major disorders of brain health in childhood, adolescence and adulthood. Research studies have identified potential 'markers' to support diagnostic, functional assessment and treatment decisions, but there is little consensus about these markers. Of these potential markers, cognitive measures of thinking functions, such as sustaining attention and associated electrical brain activity, show promise in complementing the clinical management process. Emerging evidence highlights the relevance of emotional, as well as thinking, functions to ADHD. Here, we outline an integrative neuroscience framework for ADHD that offers one means to bring together cognitive measures of thinking functions with measures of emotion, and their brain and genetic correlates. Understanding these measures and the relationships between them is a first step towards the development of tools that will help to assess the heterogeneity of ADHD, and aid in tailoring treatment choices.

Anterior cingulate activity to salient stimuli is modulated by autonomic arousal in posttraumatic stress disorder.

Reduced ventral anterior cingulate (vACC) activity to threat is thought to reflect an impairment in regulating arousal networks in posttraumatic stress disorder (PTSD). Concurrent functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording were used to examine neural functioning when arousal networks are engaged. Eleven participants with PTSD and 11 age- and sex-matched non-traumatized controls performed an oddball task that required responding to salient, non-trauma-related auditory target tones embedded in lower frequency background tones. Averaged target-background analyses revealed significantly greater dorsal ACC, supramarginal gyrus, and hippocampal activity in PTSD relative to control participants.With-SCR target responses resulted in increased vACC activity in controls, and dorsal ACC activity in PTSD. PTSD participants had reduced vACC activity relative to controls to target tones when SCR responses were present. This reduction in vACC in PTSD relative to controls was not apparent in without-SCR responses. These findings suggest that a reduction in vACC in PTSD occurs specifically when arousal networks are engaged.

Total red blood cell concentrations of omega-3 fatty acids are associated with emotion-elicited neural activity in adolescent boys with attention-deficit hyperactivity disorder.

Affective impairment is observed in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Low levels of long-chain polyunsaturated fatty acids (LC-PUFA), specifically omega-3 (omega-3) fatty acids in blood measures have been linked to a range of behavioural and mood disorders including ADHD. However, nothing is known about the relationship between omega-3 and brain function in children with ADHD. In the current study, 20 adolescent boys with ADHD were assessed for total lipid fractions in red blood cells and their event-related potential (ERP) response to the presentation of facial expressions of happiness, sadness and fearfulness. The results supported the hypothesis of a positive association between eicosapentaenoic acid (EPA) and a cognitive bias in orientation to overt expressions of happiness over both sad and fearful faces as indexed by midline frontal P300 amplitude. Additional exploratory analyses revealed a positive association between levels of docosahexaenoic acid (DHA) and the right temporal N170 amplitude in response to covert expressions of fear. The arachidonic (AA)/DHA ratio was negatively associated with the right temporal N170 amplitude also to covert expressions of fear. These findings indicate that EPA and DHA may be involved in distinct aspects of affect processing in ADHD and have implications for understanding currently inconsistent findings in the literature on EFA supplementation in ADHD and depression.

Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: evidence from cognition, the P300 and fronto-hippocampal systems.

In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.

Event-related wave activity in the EEG provides new marker of ADHD.

OBJECTIVE: This study examines the utility of new measures of event-related spatio-temporal waves in the EEG as a marker of ADHD, previously shown to be closely related to the P3 ERP in an adult sample. METHODS: Wave activity in the EEG was assessed during both an auditory Oddball and a visual continuous performance task (CPT) for an ADHD group ranging in age from 6 to 18 years and comprising mostly Combined and Inattentive subtypes, and for an age and gender matched control group. RESULTS: The ADHD subjects had less wave activity at low frequencies ( approximately 1 Hz) during both tasks. For auditory Oddball targets, this effect was shown to be related to smaller P3 ERP amplitudes. During CPT, the approximately 1 Hz wave activity in the ADHD subjects was inversely related to clinical and behavioral measures of hyperactivity and impulsivity. CPT wave activity at approximately 1 Hz was seen to "normalise" following treatment with stimulant medication. CONCLUSIONS: The results identify a deficit in low frequency wave activity as a new marker for ADHD associated with levels of hyperactivity and impulsivity. SIGNIFICANCE: The marker is evident across a range of tasks and may be specific to ADHD. While lower approximately 1 Hz activity partly accounts for reduced P3 ERPs in ADHD, the effect also arises for tasks that do not elicit a P3. Deficits in behavioral inhibition are hypothesized to arise from underlying dysregulation of cortical inhibition.

Brain structure and function correlates of general and social cognition.

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 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.

An integrative approach to determine the best behavioral and biological markers of methylphenidate.

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.

Mapping frontal-limbic correlates of orienting to change detection.

Orienting responses are elicited by salient stimuli, and may be indexed by skin conductance responses. Concurrent functional magnetic resonance imaging and skin conductance response recording was used to identify neural correlates of orienting to abrupt sensory change (infrequent high pitch oddball 'target' tones embedded in frequent lower pitch 'standard' tones) in 16 healthy participants. 'With skin conductance response' responses to targets were distinguished by preferentially greater activity in the amygdala and ventral medial and lateral frontal cortical regions. By contrast, 'without skin conductance response' responses elicited distinctive activity in the dorsal lateral frontal cortex and supramarginal gyrus. These findings suggest that orienting to unexpected sensory change elicits a network for appraising salience and novelty, whereas, in the absence of orienting, a parallel network for sensory and context evaluation is preferentially engaged.

Predicting severity of non-clinical depression: preliminary findings using an integrated approach.

INTRODUCTION: Depression is characterized by disturbances in affect, cognition, brain and body function, yet studies have tended to focus on single domains of dysfunction. An integrated approach may provide a more complete profile of the range of deficits characterized by depressed individuals, but it is unclear whether this approach is able to predict depression severity over and above that predicted by single tasks or domains of function. In this study, we examined the value of combining multiple domains of function in predicting depression severity. METHODS: Participants contained in the International Brain Database, (http://www.brainresource.com) had completed three testing components including a web-based questionnaire of Personal History, the Brain Resource Cognition battery of Neuropsychological tests, Personality assessment and Psychophysiological testing. Two hundred and sixty six of these participants were able to be classified as either non-depressed, mild-moderately or severely (non-clinically) depressed, based on a depression screening questionnaire. Analysis of variance identified variables on which the categorized participants differed. Significant variables were then entered into a series of stepwise regressions to examine their ability to predict depression scores. RESULTS: An integrated model including measures of affect (increased Neuroticism; decreased Emotional Intelligence), cognition (increased variability of reaction time during a working memory task; decreased "name the word component score" in the verbal interference task), brain (decreased left-lateralized P150 ERP component during a working memory task) and body function (increased negative skin conductance level gradient) were found to predict more of the variation in depression severity than any single domain of function. DISCUSSION: On the basis of behavioral as well as Psychophysiological findings reported in this study, it was suggested that deficits in subclinically depressed individuals are more pronounced during automatic stages of stimulus processing, and that performance in these individuals may improve (to the level displayed by controls) when task demands are increased. Findings also suggest that it is important to consider disturbances across different domains of function in order to elucidate depression severity. Each domain may contribute unique explanatory information consistent with an integrative model of depression, taking into account the role of both behavior and underlying neural changes.

Neurophysiological markers of contextual processing: the relationship between P3b and Gamma synchrony and their modulation by arousal, performance and individual differences.

The ability to identify and respond to significant events in the environment is a vital aspect of human cognition and yet is poorly understood as a dynamic neural process. While the response to a contextually-relevant stimulus involves a number of complimentary processes, including selective attention and neural binding, it is also subject to modulation by factors like arousal, age and sex. Adopting an integrative approach, we investigated contextual processing (as indexed by P3b and Gamma phase synchrony) in 120 healthy subjects performing an auditory oddball task while controlling for these other modulating factors. Results suggest a relationship between P3b and Gamma-2 synchrony in posterior regions only, with phasic anterior processing seemingly unrelated to that in posterior regions. However, only the P3b was significantly correlated to central and autonomic arousal. Further, while age and sex were associated with variation in individual measures, they did not strongly affect the relationship between the measures. We concluded that, in simple contextual processing, global and local elements of target stimuli are processed in parallel with little variation being shown between the sexes or resulting from increasing age.

Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems.

Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that incoming sensory signals of fear travel from thalamus to amygdala via two neural pathways: a direct subcortical route and an indirect pathway via the sensory cortex. Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo. We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the modulation of these networks by the anterior cingulate cortex (ACC). Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the 'baseline' control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed an inverse functional connectivity between occipito-temporal visual regions and the left amygdala, but a positive connectivity between these visual region and the right amygdala, suggesting that there is a hemispheric specialization in the transfer of fear signals from sensory cortices to amygdala. Physiophysiological interactions revealed a dorsal-ventral division in ACC modulation of the thalamus-sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship. In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus-amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

Preservation of limbic and paralimbic structures in aging.

Patterns of gray matter (GM) loss were measured in 223 healthy subjects spanning eight decades. We observed significant clusters of accelerated loss in focal regions of the frontal and parietal cortices, including the dorsolateral frontal cortex, pre- and postcentral gyrus, and the inferior and superior parietal lobes. The rate of loss in these clusters was approximately twice that of the global average. By contrast, clusters of significant GM preservation were found in limbic and paralimbic structures, including the amygdala, hippocampus, thalamus, and the cingulate gyrus. In these clusters, GM loss was attenuated significantly relative to the global rate. The preservation of these structures is consistent with the functional importance of the thalamo-limbic circuits in sensory integration, arousal, emotion, and memory, and lends credence to the idea that later-maturing cortical regions are more vulnerable to age-related morphologic changes. Moreover, the limbic findings act as a frame of reference to explore further the effects of stress and learning on these structures in an evidence-based manner across age.

"Gamma synchrony" in first-episode schizophrenia: a disorder of temporal connectivity?

OBJECTIVE: There has been a convergence of models describing schizophrenia as a disconnection syndrome, with a focus on the temporal connectivity of neural activity. Synchronous gamma-band (40-Hz) activity has been implicated as a candidate mechanism for the binding of distributed neural activity. To the authors' knowledge, this is the first study to investigate "gamma synchrony" in first-episode schizophrenia. METHOD: Forty medicated first-episode schizophrenia patients and 40 age- and sex-matched healthy comparison subjects participated in a conventional auditory oddball paradigm. Gamma synchrony, time-locked to target stimuli, was extracted from an ongoing EEG. The magnitude and latency of both early (gamma 1: -150 msec to 150 msec poststimulus) and late (gamma 2: 200 to 550 msec poststimulus) synchrony were analyzed with multiple analysis of variance. RESULTS: First-episode schizophrenia patients showed a decreased magnitude and delayed latency for global gamma 1 synchrony in relation to healthy comparison subjects. By contrast, there were no group differences in gamma 2 synchrony. CONCLUSIONS: These findings suggest that first-episode schizophrenia patients have a global decrease and delay of temporal connectivity of neural activity in early sensory response to task-relevant stimuli. This is consistent with cognitive evidence of perceptual integration deficits in this disorder and raises the possibility that a breakdown in the early synchrony of distributed neural networks is a marker for the onset of schizophrenia.

Distinct pattern of P3a event-related potential in borderline personality disorder.

P3a and P3b event-related brain potentials to auditory stimuli were recorded for 17 unmedicated patients with borderline personality disorder, 17 matched healthy controls and 100 healthy control participants spanning five decades. Using high-resolution fragmentary decomposition for single-trial event-related potential analysis, distinctive disturbances in P3a in borderline personality disorder patients were found: abnormally enhanced amplitude, failure to habituate and a loss of temporal locking with P3b. Normative age dependencies from 100 controls suggest that natural age-related decline in P3a amplitude is reduced in borderline personality disorder patients and is likely to indicate failure of frontal maturation. On the basis of the theories of Hughlings Jackson, this conceptualization of borderline personality disorder is consistent with an aetiological model of borderline personality disorder.