Identifying canonical and replicable multi-scale intrinsic connectivity networks in 100k+ resting-state fMRI datasets.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

A method for estimating and characterizing explicitly nonlinear dynamic functional network connectivity in resting-state fMRI data.

The past 10 years have seen an explosion of approaches that focus on the study of time-resolved change in functional connectivity (FC). FC characterization among networks at a whole-brain level is frequently termed functional network connectivity (FNC). Time-resolved or dynamic functional network connectivity (dFNC) focuses on the estimation of transient, recurring, whole-brain patterns of FNC. While most approaches in this area have attempted to capture dynamic linear correlation, we are particularly interested in whether explicitly nonlinear relationships, above and beyond linear, are present and contain unique information. This study thus proposes an approach to assess explicitly nonlinear dynamic functional network connectivity (EN dFNC) derived from the relationship among independent component analysis time courses. Linear relationships were removed at each time point to evaluate, typically ignored, explicitly nonlinear dFNC using normalized mutual information (NMI). Simulations showed the proposed method estimated explicitly nonlinearity over time, even within relatively short windows of data. We then, applied our approach on 151 schizophrenia patients, and 163 healthy controls fMRI data and found three unique, highly structured, mostly long-range, functional states that also showed significant group differences. In particular, explicitly nonlinear relationships tend to be more widespread than linear ones. Results also highlighted a state with long range connections to the visual domain, which were significantly reduced in schizophrenia. Overall, this work suggests that quantifying EN dFNC may provide a complementary and potentially valuable tool for studying brain function by exposing relevant variation that is typically ignored.

Effects of gonadal steroids on reward circuitry function and anhedonia in women with a history of postpartum depression.

BACKGROUND: Reward system dysfunction is evident across neuropsychiatric conditions. Here we present data from a double-blinded pharmaco-fMRI study investigating the triggering of anhedonia and reward circuit activity in women. METHODS: The hormonal states of pregnancy and parturition were simulated in euthymic women with a history of postpartum depression (PPD+; n = 15) and those without such a history (PPD-; n = 15) by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks ("addback"), and then withdrawing both steroids ("withdrawal"). Anhedonia was assessed using the Inventory of Depression and Anxiety Symptoms (IDAS) during each hormone phase. Those who reported a 30 % or greater increase in IDAS anhedonia, dysphoria, or ill temper during addback or withdrawal, compared with pre-treatment, were identified as hormone sensitive (HS+) and all others were identified as non-hormone sensitive (HS-). The monetary incentive delay (MID) task was administered during fMRI sessions at pre-treatment and during hormone withdrawal to assess brain activation during reward anticipation and feedback. RESULTS: On average, anhedonia increased during addback and withdrawal in PPD+ but not PPD-. During reward feedback, both HS+ (n = 10) and HS- (n = 18) showed decreased activation in clusters in the right putamen (p < .031, FWE-corrected) and left postcentral and supramarginal gyri (p < .014, FWE-corrected) at the withdrawal scans, relative to pre-treatment scans. LIMITATIONS: A modest sample size, stringent exclusion criteria, and relative lack of diversity in study participants limit the generalizability of results. CONCLUSION: Although results do not explain differential hormone sensitivity in depression, they demonstrate significant effects of reproductive hormones on reward-related brain function in women.

Moving beyond the 'CAP' of the Iceberg: Intrinsic connectivity networks in fMRI are continuously engaging and overlapping.

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

Resting-state thalamic dysconnectivity in schizophrenia and relationships with symptoms.

BACKGROUND: Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities. METHOD: Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined. RESULTS: HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior. CONCLUSIONS: Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.

Abnormal Neural Activation to Faces in the Parents of Children with Autism.

Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the "Broad Autism Phenotype " (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally in autism parents with aloof personality ("BAP+"). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP.

Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia.

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical-subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.

fMRI activity correlated with auditory hallucinations during performance of a working memory task: data from the FBIRN consortium study.

INTRODUCTION: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. METHODS: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. RESULTS: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. DISCUSSION: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study.

BACKGROUND: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

Auditory oddball deficits in schizophrenia: an independent component analysis of the fMRI multisite function BIRN study.

Deficits in the connectivity between brain regions have been suggested to play a major role in the pathophysiology of schizophrenia. A functional magnetic resonance imaging (fMRI) analysis of schizophrenia was implemented using independent component analysis (ICA) to identify multiple temporally cohesive, spatially distributed regions of brain activity that represent functionally connected networks. We hypothesized that functional connectivity differences would be seen in auditory networks comprised of regions such as superior temporal gyrus as well as executive networks that consisted of frontal-parietal areas. Eight networks were found to be implicated in schizophrenia during the auditory oddball paradigm. These included a bilateral temporal network containing the superior and middle temporal gyrus; a default-mode network comprised of the posterior cingulate, precuneus, and middle frontal gyrus; and multiple dorsal lateral prefrontal cortex networks that constituted various levels of between-group differences. Highly task-related sensory networks were also found. These results indicate that patients with schizophrenia show functional connectivity differences in networks related to auditory processing, executive control, and baseline functional activity. Overall, these findings support the idea that the cognitive deficits associated with schizophrenia are widespread and that a functional connectivity approach can help elucidate the neural correlates of this disorder.

Task specific influences of Parkinson's disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries.

The motor deficits in Parkinson's disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [(123)I](-)-2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of functional magnetic resonance imaging (fMRI) data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twin's activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (cerebellar-cortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG-cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar-cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG-cortical and cerebellar-cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG-cortical pathway, but "over-corrected" the activation in the ipsilateral BG-cortical and bilateral cerebellar-cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG-cortical and cerebellar-cortical pathways are task-specifically influenced by PD. The levodopa-induced "over-activation" of BG-cortical and cerebellar-cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration.

The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches.

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

Prefrontal activation evoked by infrequent target and novel stimuli in a visual target detection task: an event-related functional magnetic resonance imaging study.

An event-related functional magnetic resonance imaging study of prefrontal cortex was conducted during which subjects performed a visual "oddball" target detection task. Exemplars of three stimulus categories were presented at a rate of one per 1.5 sec for 10 runs, each consisting of 132 trials. Standards were color squares of varying sizes that were presented on approximately 92% of trials. Targets were color circles of varying sizes presented irregularly on approximately 4% of trials. Novels were pictures of everyday objects that were also presented irregularly on approximately 4% of trials. Ten subjects participated in two separate sessions in which they were required to count mentally or to push a button whenever a target appeared. Targets evoked activation within prefrontal cortex, primarily within the middle frontal gyri (MFG). This MFG activation did not differ as a function of the required response. Novels did not evoke significant activity within this region despite evidence from a separate behavioral and event-related potential study demonstrating their strong influence on processing. In additional imaging sessions with two subjects, the rules were reversed to require a button press whenever an object, but not a circle, appeared. These former novels now evoked activation in the MFG, but the former target circles did not. These experiments indicate that MFG activation is reliably evoked by exemplars from arbitrary stimulus categories that are mapped by experimental rules onto an arbitrary covert or overt response.

Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions.

BACKGROUND: The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations. METHODS: In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo. RESULTS: In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency. CONCLUSIONS: This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.

NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.

Electrophysiological studies of human face perception. II: Response properties of face-specific potentials generated in occipitotemporal cortex.

In the previous paper the locations and basic response properties of N200 and other face-specific event-related potentials (ERPs) were described. In this paper responsiveness of N200 and related ERPs to the perceptual features of faces and other images was assessed. N200 amplitude did not vary substantially, whether evoked by colored or grayscale faces; normal, blurred or line-drawing faces; or by faces of different sizes. Human hands evoked small N200s at face-specific sites, but evoked hand-specific ERPs at other sites. Cat and dog faces evoked N200s that were 73% as large as to human faces. Hemifield stimulation demonstrated that the right hemisphere is better at processing information about upright faces and transferring it to the left hemisphere, whereas the left hemisphere is better at processing information about inverted faces and transferring it to the right hemisphere. N200 amplitude was largest to full faces and decreased progressively to eyes, face contours, lips and noses viewed in isolation. A region just lateral to face-specific N200 sites was more responsive to internal face parts than to faces, and some sites in ventral occipitotemporal cortex were face-part-specific. Faces with eyes averted or closed evoked larger N200s than those evoked by faces with eyes forward. N200 amplitude and latency were affected by the joint effects of eye and head position in the right but not in the left hemisphere. Full and three-quarter views of faces evoked larger N200s than did profile views. The results are discussed in relation to behavioral studies in humans and single-cell recordings in monkeys.

Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices".

BACKGROUND: Prior studies suggest that auditory hallucinations of "voices" arise from activation of speech perception areas of the cerebral cortex. Low frequency transcranial magnetic stimulation (TMS) can reduce cortical activation. METHODS: We have studied three schizophrenic patients reporting persistent auditory hallucinations to determine if low frequency TMS could curtail these experiences. One hertz stimulation of left temporoparietal cortex was compared with sham stimulation using a double-blind, cross-over design. RESULTS: All three patients demonstrated greater improvement in hallucination severity following active stimulation compared to sham stimulation. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. CONCLUSIONS: TMS may advance our understanding of the mechanism and treatment of auditory hallucinations.

Midlatency evoked potentials attenuation and augmentation reflect different aspects of sensory gating.

A broad definition of sensory gating refers to the ability of the brain to modulate its sensitivity to incoming sensory stimuli. This definition allows the concept of gating to include both the capacities to minimize or stop responding to incoming irrelevant stimuli (gating out) and to respond when a novel stimulus is presented or a change occurs in ongoing stimuli (gating in). In order to further characterize the function of sensory gating, we examined the attenuation (decreased responding) and augmentation (increased responding) of the P50 EP amplitudes in 22 normal volunteers. Three EP paradigms, each including a number of conditions, designed to examine both EP habituation (inhibition) and dishabituation (excitation) were administered to each subject. In conditions designed to examine habituation (identical pairs of clicks or trains of repetitive identical clicks), the P50 behaved, as expected, with decrease of the amplitude with repetition. In conditions designed to examine dishabituation the amplitude of the P50, EP did not decrease as much (and frequently increased) with stimulus change. The results suggest that the P50 EP is sensitive to the effects of stimulus repetition and stimulus change and can be used to study the different aspects of sensory gating.

Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report.

Dysfunction of sensory gating has been implicated in the pathophysiology of schizophrenia. The goal of this study was to provide evidence that sensory gating dysfunction in schizophrenia patients is a compounded problem with difficulty in filtering out irrelevant input and filtering in relevant input at both an early-preattentive stage and a later, early-attentive stage of information processing. Four components of sensory gating were examined in 12 medicated, stable schizophrenia patients and 12 age- and sex-matched normal control subjects. Evoked potential paradigms designed to examine the effects of stimulus repetition and stimulus change were utilized. Attenuation of the amplitude of the P50 and the N100 evoked potentials with stimulus repetition was significantly decreased in schizophrenia patients as compared to normal control subjects. The presentation of deviant stimuli caused the degree of attenuation to decrease in normal subjects. This effect was much decreased (and at times reversed) in schizophrenia subjects. These data suggest that schizophrenia patients have difficulty inhibiting incoming, irrelevant stimuli and responding to incoming, significant input as measured by preattentive EPs (P50). The data also suggest that similar abnormalities can be demonstrated at a slightly later phase of information processing (i.e. early-attentive phase) using the N100 EP.

Dissociation of mnemonic and perceptual processes during spatial and nonspatial working memory using fMRI.

Neuroimaging studies in humans have consistently found robust activation of frontal, parietal, and temporal regions during working memory tasks. Whether these activations represent functional networks segregated by perceptual domain is still at issue. Two functional magnetic resonance imaging experiments were conducted, both of which used multiple-cycle, alternating task designs. Experiment 1 compared spatial and object working memory tasks to identify cortical regions differentially activated by these perceptual domains. Experiment 2 compared working memory and perceptual control tasks within each of the spatial and object domains to determine whether the regions identified in experiment 1 were driven primarily by the perceptual or mnemonic demands of the tasks, and to identify common brain regions activated by working memory in both perceptual domains. Domain-specific activation occurred in the inferior parietal cortex for spatial tasks, and in the inferior occipitotemporal cortex for object tasks, particularly in the left hemisphere. However, neither area was strongly influenced by task demands, being nearly equally activated by the working memory and perceptual control tasks. In contrast, activation of the dorsolateral prefrontal cortex and the intraparietal sulcus (IPS) was strongly task-related. Spatial working memory primarily activated the right middle frontal gyrus (MFG) and the IPS. Object working memory activated the MFG bilaterally, the left inferior frontal gyrus, and the IPS, particularly in the left hemisphere. Finally, activation of midline posterior regions, including the cingulate gyrus, occurred at the offset of the working memory tasks, particularly the shape task. These results support a prominent role of the prefrontal and parietal cortices in working memory, and indicate that spatial and object working memory tasks recruit differential hemispheric networks. The results also affirm the distinction between spatial and object perceptual processing in dorsal and ventral visual pathways.