Auditory Oddball Responses Across the Schizophrenia-Bipolar Spectrum and Their Relationship to Cognitive and Clinical Features.

OBJECTIVE: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features. METHODS: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2). RESULTS: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups. CONCLUSIONS: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

Dynamic functional network reconfiguration underlying the pathophysiology of schizophrenia and autism spectrum disorder.

The dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step-wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole-brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ-ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning-problem-solving performance in SZ (r = -.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders.

Alterations in intrinsic fronto-thalamo-parietal connectivity are associated with cognitive control deficits in psychotic disorders.

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well-established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting-state magnetic resonance imaging study (rs-MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well-established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs-MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole-brain functional connectivity (FC) analysis. Altered FC was observed in a fronto-thalamo-parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting-state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto-thalamo-parietal network activation during antisaccade performance seen in task-based fMRI studies.

The effect of high-dose atorvastatin on neural activity and cognitive function.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has not been used to assess the effects of statins on the brain. We assessed the effect of statins on cognition using standard neuropsychological assessments and brain neural activation with fMRI on two tasks. METHODS: Healthy statin-naïve men and women (48±15 years) were randomized to 80 mg/day atorvastatin (n=66; 27 men) or placebo (n=84; 48 men) for 6 months. Participants completed cognitive testing while on study drug and 2 months after treatment cessation using alternative test and task versions. RESULTS: There were few changes in standard neuropsychological tests with drug treatment (all P>.56). Total and delayed recall from the Hopkins Verbal Learning Test-Revised increased in both groups (P<.05). The Stroop Color-Word score increased (P<.01) and the 18-Point Clock Test decreased in the placebo group (P=.02) after drug cessation. There were, however, small but significant group-time interactions for each fMRI task: participants on placebo had greater activation in the right putamen/dorsal striatum during the maintenance phase of the Sternberg task while on placebo but the effect was reversed after drug washout (P<.001). Participants on atorvastatin had greater activation in the bilateral precuneus during the encoding phase of the Figural Memory task while on-drug but the effect was reversed after drug washout (P<.001). CONCLUSION: Six months of high dose atorvastatin therapy is not associated with measurable changes in neuropsychological test scores, but did evoke transient differences in brain activation patterns. Larger, longer-term clinical trials are necessary to confirm these findings and evaluate their clinical implications.

Pupillometer-based neurofeedback cognitive training to improve processing speed and social functioning in individuals at clinical high risk for psychosis.

OBJECTIVE: Among individuals at clinical high risk (CHR) for psychosis, processing speed (PS) has been related to social and role functioning regardless of conversion to schizophrenia. This information processing dysfunction is a gateway to broader behavioral deficits such as difficulty executing social behaviors. We examined the feasibility of improving information processing relevant to social situations in CHR, including its sustainability at 2-month follow-up, and its association with concurrent social function. METHOD: This was a double-blind RCT in which 62 CHR participants were randomized to Processing Speed Training (PST) or an active control matched for training format and the same dose and duration of treatment. PST is a tablet-based program that uses pupillometry-based neurofeedback to continually adjust training parameters for an optimal neurocognitive load and to improve visual scanning efficiency by inhibiting selection of nonessential targets and discriminating figure-ground details. RESULTS: The PST group showed faster motoric and nonmotoric PS at post training and 2-month follow-up. At 2 month follow-up, the PST group reported better overall social adjustment. Changes in PS from baseline to 2 months were correlated with overall social adjustment and social avoidance in the entire sample. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This is the first study to test focal neurofeedback-based cognitive training for PS deficits in the putatively prodromal phase of schizophrenia to address associated social morbidity. Targeting PS appears to be a promising pathway to decreasing comorbidity and mitigating a risk factor for psychosis. (PsycINFO Database Record

Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers.

OBJECTIVE: Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations. METHOD: A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected. RESULTS: Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders. CONCLUSIONS: These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.

Event-related potential and time-frequency endophenotypes for schizophrenia and psychotic bipolar disorder.

BACKGROUND: The investigators compared event-related potential (ERP) amplitudes and event-related oscillations across a broad frequency range during an auditory oddball task using a comprehensive analysis approach to describe shared and unique neural auditory processing characteristics among healthy subjects (HP), schizophrenia probands (SZ) and their first-degree relatives, and bipolar disorder I with psychosis probands (BDP) and their first-degree relatives. METHODS: This Bipolar-Schizophrenia Network on Intermediate Phenotypes sample consisted of clinically stable SZ (n = 229) and BDP (n = 188), HP (n = 284), first-degree relatives of schizophrenia probands (n = 264), and first-degree relatives of bipolar disorder I with psychosis probands (n = 239). They were administered an auditory oddball task in the electroencephalography environment. Principal components analysis derived data-driven frequency bands evoked power. Spatial principal components analysis reduced ERP and frequency data to component waveforms for each subject. Clusters of time bins with significant group differences on response magnitude were assessed for proband/relative differences from HP and familiality. RESULTS: Nine variables survived a linear discriminant analysis between HP, SZ, and BDP. Of those, two showed evidence (deficit in relatives and familiality) as genetic risk markers more specific to SZ (N1, P3b), one was specific to BDP (P2) and one for psychosis in general (N2). CONCLUSIONS: This study supports for both shared and unique deficits in early sensory and late cognitive processing across psychotic diagnostic groups. Additional ERP and time-frequency component alterations (frontal N2/P2, late high, early, mid, and low frequency) may provide insight into deficits in underlying neural architecture and potential protective/compensatory mechanisms in unaffected relatives.

Patients with schizophrenia demonstrate reduced cortical sensitivity to auditory oddball regularities.

BACKGROUND: Individuals with schizophrenia demonstrate deficits in context processing. These deficits can be characterized by examining the influence of auditory context on ERP responses to rare target tones. Previous studies demonstrate that target ERP deficits in schizophrenia depend on the number of non-targets that precede the target ERP. Our goal was to extend these findings by examining whether patients with schizophrenia demonstrate a reduced sensitivity to subtle differences in the auditory context preceding rare target stimuli, as quantified by Itti and Baldi's Bayesian prediction error model. METHODS: Cortical responses to auditory oddball tones were measured within 59 individuals with schizophrenia (SZ) and 59 controls (HC). Individual trial amplitudes were estimated by conducting group ICA on the EEG time series and analyzing the reconstructed individual temporal sources. We quantified the auditory context of target tones using the Bayesian prediction error model and determined whether ERP amplitudes to tones were sensitive to this measure of context, or the number of preceding non-targets directly, within HC and SZ. RESULTS: Individuals with schizophrenia show a significant reduction in ERP response amplitudes to targets approximately 244-412 ms following target onsets. Individual amplitudes within this window showed significantly greater sensitivity to the modeled prediction error within the controls than in individuals with schizophrenia. These differences approached significance when examining differences in amplitudes as a function of the number of preceding non-targets. CONCLUSIONS: These findings further clarify differences in HC and SZ with regard to their attentional and perceptual sensitivity to subtle environmental regularities.

Thalamic fractional anisotropy predicts accrual of cerebral white matter damage in older subjects with small-vessel disease.

White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (⩾75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of baseline thalamic FA in multivariate modeling increased this value by 70%, which explains 46.5% of the variance in WMH accrual rate. Thalamic FA might serve as a novel predictor of cerebral small-vessel disease progression in clinical settings and trials. Furthermore, our findings point to the possibility of a causal relationship between thalamic damage and the accrual of WMHs.

Thalamus and posterior temporal lobe show greater inter-network connectivity at rest and across sensory paradigms in schizophrenia.

Although a number of recent studies have examined functional connectivity at rest, few have assessed differences between connectivity both during rest and across active task paradigms. Therefore, the question of whether cortical connectivity patterns remain stable or change with task engagement continues to be unaddressed. We collected multi-scan fMRI data on healthy controls (N=53) and schizophrenia patients (N=42) during rest and across paradigms arranged hierarchically by sensory load. We measured functional network connectivity among 45 non-artifactual distinct brain networks. Then, we applied a novel analysis to assess cross paradigm connectivity patterns applied to healthy controls and patients with schizophrenia. To detect these patterns, we fit a group by task full factorial ANOVA model to the group average functional network connectivity values. Our approach identified both stable (static effects) and state-based differences (dynamic effects) in brain connectivity providing a better understanding of how individuals' reactions to simple sensory stimuli are conditioned by the context within which they are presented. Our findings suggest that not all group differences observed during rest are detectable in other cognitive states. In addition, the stable differences of heightened connectivity between multiple brain areas with thalamus across tasks underscore the importance of the thalamus as a gateway to sensory input and provide new insight into schizophrenia.

Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness.

Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory-motor cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-striatal-cerebellar regions relative to controls, possibly reflective of sensory gating and top-down control disturbances. Clustering revealed that this dysconnectivity was prominent for thalamic nuclei densely connected with the prefrontal cortex. Classification and cross-diagnostic results suggest that thalamic dysconnectivity may be a neural marker for disturbances across diagnoses. Present findings, using one of the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness.

Family history of psychosis moderates early auditory cortical response abnormalities in non-psychotic bipolar disorder.

OBJECTIVES: Bipolar I disorder is a disabling illness affecting 1% of people worldwide. Family and twin studies suggest that psychotic bipolar disorder (BDP) represents a homogeneous subgroup with an etiology distinct from non-psychotic bipolar disorder (BDNP) and partially shared with schizophrenia. Studies of auditory electrophysiology [e.g., paired-stimulus and oddball measured with electroencephalography (EEG)] consistently report deviations in psychotic groups (schizophrenia, BDP), yet such studies comparing BDP and BDNP are sparse and, in some cases, conflicting. Auditory EEG responses are significantly reduced in unaffected relatives of psychosis patients, suggesting that they may relate to both psychosis liability and expression. METHODS: While 64-sensor EEGs were recorded, age- and gender-matched samples of 70 BDP, 35 BDNP {20 with a family history of psychosis [BDNP(+)]}, and 70 psychiatrically healthy subjects were presented with typical auditory paired-stimuli and auditory oddball paradigms. RESULTS: Oddball P3b reductions were present and indistinguishable across all patient groups. P2s to paired stimuli were abnormal only in BDP and BDNP(+). Conversely, N1 reductions to stimuli in both paradigms and P3a reductions were present in both BDP and BDNP(-) groups but were absent in BDNP(+). CONCLUSIONS: Although nearly all auditory neural response components studied were abnormal in BDP, BDNP abnormalities at early- and mid-latencies were moderated by family psychosis history. The relationship between psychosis expression, heritable psychosis risk, and neurophysiology within bipolar disorder, therefore, may be complex. Consideration of such clinical disease heterogeneity may be important for future investigations of the pathophysiology of major psychiatric disturbance.

Glycine treatment of the risk syndrome for psychosis: report of two pilot studies.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.

Decreased prefrontal cortex activity in mild traumatic brain injury during performance of an auditory oddball task.

Up to one-third of patients with mild traumatic brain injury (TBI) demonstrate persistent cognitive deficits in the 'executive' function domain. Mild TBI patients have shown prefrontal cortex activity deficits during the performance of executive tasks requiring active information maintenance and manipulation. However, it is unclear whether these deficits are related to the executive processes themselves, or to the degree of mental effort. To determine whether prefrontal deficits also would be found during less effortful forms of executive ability, fMRI images were obtained on 31 mild TBI patients and 31 control participants during three-stimulus auditory oddball task performance. Although patients and controls had similar topographical patterns of brain activity, region-of-interest analysis revealed significantly decreased activity in right dorsolateral prefrontal cortex for mild TBI patients during target stimulus detection. Between-group analyses found evidence for potential compensatory brain activity during target detection and default-mode network dysfunction only during the detection of novel stimuli.

A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia.

Understanding genetic influences on both healthy and disordered brain function is a major focus in psychiatric neuroimaging. We utilized task-related imaging findings from an fMRI auditory oddball task known to be robustly associated with abnormal activation in schizophrenia, to investigate genomic factors derived from multiple single nucleotide polymorphisms (SNPs) from genes previously shown to be associated with schizophrenia. Our major aim was to investigate the relationship of these genomic factors to normal/abnormal brain functionality between controls and schizophrenia patients. We studied a Caucasian-only sample of 35 healthy controls and 31 schizophrenia patients. All subjects performed an auditory oddball task, which consists of detecting an infrequent sound within a series of frequent sounds. Each subject was characterized on 24 different SNP markers spanning multiple risk genes previously associated with schizophrenia. We used a recently developed technique named parallel independent component analysis (para-ICA) to analyze this multimodal data set (Liu et al., 2008). The method aims to identify simultaneously independent components of each modality (functional imaging, genetics) and the relationships between them. We detected three fMRI components significantly correlated with two distinct gene components. The fMRI components, along with their significant genetic profile (dominant SNP) correlations were as follows: (1) Inferior frontal-anterior/posterior cingulate-thalamus-caudate with SNPs from Brain derived neurotropic factor (BDNF) and dopamine transporter (DAT) [r=-0.51; p<0.0001], (2) superior/middle temporal gyrus-cingulate-premotor with SLC6A4_PR and SLC6A4_PR_AG (serotonin transporter promoter; 5HTTLPR) [r=0.27; p=0.03], and (3) default mode-fronto-temporal gyrus with Brain derived neurotropic factor and dopamine transporter (BDNF, DAT) [r=-0.25; p=0.04]. Functional components comprised task-relevant regions (including PFC, ACC, STG and MTG) frequently identified as abnormal in schizophrenia. Further, gene-fMRI combinations 1 (Z=1.75; p=0.03), 2 (Z=1.84; p=0.03) and 3 (Z=1.67; p=0.04) listed above showed significant differences between controls and patients, based on their correlated loading coefficients. We demonstrate a framework to identify interactions between "clusters" of brain function and of genetic information. Our results reveal the effect/influence of specific interactions, (perhaps epistastatic in nature), between schizophrenia risk genes on imaging endophenotypes representing attention/working memory and goal directed related brain function, thus establishing a useful methodology to probe multivariate genotype-phenotype relationships.

Modulation of temporally coherent brain networks estimated using ICA at rest and during cognitive tasks.

Brain regions which exhibit temporally coherent fluctuations, have been increasingly studied using functional magnetic resonance imaging (fMRI). Such networks are often identified in the context of an fMRI scan collected during rest (and thus are called "resting state networks"); however, they are also present during (and modulated by) the performance of a cognitive task. In this article, we will refer to such networks as temporally coherent networks (TCNs). Although there is still some debate over the physiological source of these fluctuations, TCNs are being studied in a variety of ways. Recent studies have examined ways TCNs can be used to identify patterns associated with various brain disorders (e.g. schizophrenia, autism or Alzheimer's disease). Independent component analysis (ICA) is one method being used to identify TCNs. ICA is a data driven approach which is especially useful for decomposing activation during complex cognitive tasks where multiple operations occur simultaneously. In this article we review recent TCN studies with emphasis on those that use ICA. We also present new results showing that TCNs are robust, and can be consistently identified at rest and during performance of a cognitive task in healthy individuals and in patients with schizophrenia. In addition, multiple TCNs show temporal and spatial modulation during the cognitive task versus rest. In summary, TCNs show considerable promise as potential imaging biological markers of brain diseases, though each network needs to be studied in more detail.

An FMRI auditory oddball study of combined-subtype attention deficit hyperactivity disorder.

OBJECTIVE: Studies of attention deficit hyperactivity disorder (ADHD) have reliably found reduced amplitude event-related potentials (ERPs) measuring attention-related brain function, indicating impairment in the brain's ability to automatically orient attention to odd or novel environmental stimuli and to represent that information in working memory. However, the relationship between abnormal neurocognition and dysfunction in specific brain regions in ADHD remains unclear. METHOD: The authors used functional magnetic resonance imaging (fMRI) to identify brain regions with abnormal hemodynamic activity during processing of target and novelty oddball stimuli that engage attention. Forty-six boys 11-18 years of age participated in the study, including 23 diagnosed as having ADHD with hyperactivity and impulsivity (combined type) and 23 demographically matched control subjects. Event-related fMRI data were collected while participants performed a three-stimulus auditory oddball task. Hemodynamic activity was compared between ADHD participants and control subjects in brain regions previously linked to P3 ERPs. RESULTS: Participants with ADHD showed deficits in brain activity elicited by infrequent attentionally engaging stimuli in regions associated with attentional orienting and working-memory cognitive processes. These deficits co-occurred with highly variable and slow task performance. CONCLUSIONS: This study links ADHD attentional orienting and working-memory deficits to dysfunction in specific cortical brain regions. The results indicate that ADHD pathophysiology impairs brain systems that are important for allocating attention and using cognitive representations to guide cognition and behavior. Attention-related neural dysfunction is thus an important factor to consider in neurobiological theories of ADHD.

Aberrant "default mode" functional connectivity in schizophrenia.

OBJECTIVE: The "default mode" has been defined as a baseline condition of brain function and is of interest because its component brain regions are believed to be abnormal in schizophrenia. It was hypothesized that the default mode network would show abnormal activation and connectivity in patients with schizophrenia. METHOD: Patients with schizophrenia (N=21) and healthy comparison subjects (N=22) performed an auditory oddball task during functional magnetic resonance imaging (fMRI). Independent component analysis was used to identify the default mode component. Differences in the spatial and temporal aspects of the default mode network were examined in patients versus comparison subjects. RESULTS: Healthy comparison subjects and patients had significant spatial differences in the default mode network, most notably in the frontal, anterior cingulate, and parahippocampal gyri. In addition, activity in patients in the medial frontal, temporal, and cingulate gyri correlated with severity of positive symptoms. The patients also showed significantly higher frequency fluctuations in the temporal evolution of the default mode. CONCLUSIONS: Schizophrenia is associated with altered temporal frequency and spatial location of the default mode network. The authors hypothesized that this network may be under- or overmodulated by key regions, including the anterior and posterior cingulate cortex. In addition, the altered temporal fluctuations in patients may result from a change in the connectivity of these regions with other brain networks.

Neural correlates of the object-recall process in semantic memory.

The recall of an object from features is a specific operation in semantic memory in which the thalamus and pre-supplementary motor area (pre-SMA) are integrally involved. Other higher-order semantic cortices are also likely to be involved. We used the object-recall-from-features paradigm, with more sensitive scanning techniques and larger sample size, to replicate and extend our previous results. Eighteen right-handed healthy participants performed an object-recall task and an association semantic task, while undergoing functional magnetic resonance imaging. During object-recall, subjects determined whether words pairs describing object features combined to recall an object; during the association task they decided if two words were related. Of brain areas specifically involved in object recall, in addition to the thalamus and pre-SMA, other regions included the left dorsolateral prefrontal cortex, inferior parietal lobule, and middle temporal gyrus, and bilateral rostral anterior cingulate and inferior frontal gyri. These regions are involved in semantic processing, verbal working memory and response-conflict detection and monitoring. The thalamus likely helps to coordinate activity of these different brain areas. Understanding the circuit that normally mediates this process is relevant for schizophrenia, where many regions in this circuit are functionally abnormal and semantic memory is impaired.

Functional MRI study of a serial reaction time task in Huntington's disease.

The aim of this study was to investigate pathophysiological changes at an early stage of clinical Huntington's disease (HD) using a functional magnetic resonance imaging (fMRI) study and a serial reaction time task paradigm. Mildly affected and presymptomatic HD subjects (n = 8) and healthy normal controls (NC, n = 12) were studied. A group behavioral effect of implicit learning was seen only in the control population. Individual statistical parametric mapping (SPM) analysis showed more consistent activation of the caudate nucleus and putamen in the NC group. In the HD group, the group average SPM showed significant activation in the right head of caudate nucleus, as well as bilateral thalami, left middle temporal, right superior temporal, right superior frontal, right middle and inferior frontal and right postcentral gyri. In the comparison of between-group differences (NC-HD), reduced activation in the HD group relative to NC was observed in the right middle frontal, left middle occipital, left precuneus, and left middle frontal gyri. The variable striatal activity in the Huntington's group suggests early functional loss possibly associated with previously demonstrated early atrophy of these same neural structures.