RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias.

BACKGROUND: Schizophrenia is characterized by hallucinations, delusions and disorganized behaviour. Recessive or X-linked transmissions are rarely described for common psychiatric disorders. We examined the genetics of psychosis to identify rare large-effect variants in patients with extreme schizophrenia. METHODS: We recruited 2 consanguineous families, each with patients affected by early-onset, severe, treatment-resistant schizophrenia. We performed exome sequencing for all participants. We checked variant rarity in public databases and with ethnically matched controls. We performed in silico analyses to assess the effects of the variants on proteins. RESULTS: Structured clinical evaluations supported diagnoses of schizophrenia in all patients and phenotypic absence in the unaffected individuals. Data analyses identified multiple variants. Only 1 variant per family was predicted as pathogenic by prediction tools. A homozygous c.649C > T:p.(Arg217Cys) variant in RGS3 and a hemizygous c.700A > G:p.(Thr234Ala) variant in IL1RAPL1 affected evolutionary conserved amino acid residues and were the most likely causes of phenotype in the patients of each family. Variants were ultra-rare in publicly available databases and absent from the DNA of 400 ethnically matched controls. RGS3 is implicated in modulating sensory behaviour in Caenorhabditis elegans. Variants of IL1RAPL1 are known to cause nonsyndromic X-linked intellectual disability with or without human behavioural dysfunction. LIMITATIONS: Each variant is unique to a particular family's patients, and findings may not be replicated. CONCLUSION: Our work suggests that some rare variants may be involved in causing inherited psychosis or schizophrenia. Variant-specific functional studies will elucidate the pathophysiology relevant to schizophrenias and motivate translation to personalized therapeutics.

Preliminary studies on apparent mendelian psychotic disorders in consanguineous families.

BACKGROUND: Psychiatric disorders are characterized by alteration in emotions, mood and behavior. Genetics is known to play a significant role in the development of psychiatric disorders. Genome-wide association studies have identified several loci associated with psychiatric illnesses. We hypothesize the existence of rare variants following Mendelian recessive mode of inheritance. These variants can be identified in families with multiple affected individuals born to unaffected consanguineous parents. METHODS: We visited psychiatric outpatient departments of multiple hospitals in Lahore, Pakistan. We focused on psychosis, as it can occur in several DSM disorders such as schizophrenia, dementia and bipolar disorder. After clinical diagnosis by an American trained psychiatrist, detailed clinical assessments using Diagnostic Interview for Genetic Studies (DIGS), Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD), Positive and Negative Syndrome Scale (PANSS), Hamilton Depression and Anxiety Rating Scale (HAM-D; HAM-A) were administered to all willing affected and unaffected participants. RESULTS: We identified eight pedigrees with two or more psychotic individuals in each family. Clinical diagnoses determined by their psychiatrists included ten individuals with schizophrenia; four individuals with psychosis and bipolar disorder; and two patients with "unspecified psychosis." The rating instruments rigorously confirmed the diagnosis of psychosis in the affected patients from the six families as well as the absence of psychotic disorders in unaffected individuals from the six families. We obtained DNA samples from willing members of all eight families for future genetic analyses. CONCLUSION: Our research highlights an alternative approach to discovery of rare recessively inherited genetic variants causing psychiatric disorders that have remained unidentified to date. These findings could illuminate underlying biological mechanisms leading toward development of targeted therapies in future.

Ketamine-enhanced prolonged exposure therapy in veterans with PTSD: A randomized controlled trial protocol.

BACKGROUND: The 2023 VA/DoD Clinical Practice Guideline for the Management of PTSD recommends individual, manualized trauma-focused such as Prolonged Exposure (PE) over pharmacologic interventions for the primary treatment of PTSD. Unfortunately, clinical trials of trauma-based therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate clinically meaningful symptom change. Ketamine, an FDA-approved anesthetic with potent non-competitive glutamatergic N-methyl-d-aspartate antagonistic properties, has demonstrated to enhance the recall of extinction learning and decrease fear renewal without interference of extinction training in preclinical studies. METHODS: We plan to conduct a single site RCT comparing three ketamine treatment vs. active placebo (midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start simultaneously with PE session 1. Infusions will be administered 24 h. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts during PE therapy. DISCUSSION: Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub-PTSD populations that most likely benefit from this intervention.

Genome Sequencing of Consanguineous Family Implicates Ubiquitin-Specific Protease 53 (USP53) Variant in Psychosis/Schizophrenia: Wild-Type Expression in Murine Hippocampal CA 1-3 and Granular Dentate with AMPA Synapse Interactions.

Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)-5] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1-3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia.

Evidence for intact local connectivity but disrupted regional function in the occipital lobe in children and adolescents with schizophrenia.

It has long been known that specific visual frequencies result in greater blood flow to the striate cortex. These peaks are thought to reflect synchrony of local neuronal firing that is reflective of local cortical networks. Since disrupted neural connectivity is a possible etiology for schizophrenia, our goal was to investigate whether localized connectivity, as measured by aberrant synchrony, is abnormal in children and adolescents with schizophrenia. Subjects included 25 children and adolescents with schizophrenia and 39 controls matched for age and gender. Subjects were scanned on a Siemens 3 Tesla Trio scanner while observing flashing checkerboard presented at either 1, 4, 8, or 12 Hz. Image processing included both a standard GLM model and a Fourier transform analysis. Patients had significantly smaller volume of activation in the occipital lobe compared to controls. There were no differences in the integral or percent signal change of the hemodynamic response function for each of the four frequencies. Occipital activation was stable during development between childhood and late adolescence. Finally, both patients and controls demonstrated an increased response between 4 and 8 Hz consistent with synchrony or entrainment in the neuronal response. Children and adolescents with schizophrenia had a significantly lower volume of activation in the occipital lobe in response to the flashing checkerboard task. However, features of intact local connectivity in patients, such as the hemodynamic response function and maximal response at 8 Hz, were normal. These results are consistent with abnormalities in regional connectivity with preserved local connectivity in early-onset schizophrenia.

Dissociable systems of working memory for rhythm and melody.

Specialized neural systems are engaged by the rhythmic and melodic components of music. Here, we used PET to measure regional cerebral blood flow (rCBF) in a working memory task for sequences of rhythms and melodies, which were presented in separate blocks. Healthy subjects, without musical training, judged whether a target rhythm or melody was identical to a series of subsequently presented rhythms or melodies. When contrasted with passive listening to rhythms, working memory for rhythm activated the cerebellar hemispheres and vermis, right anterior insular cortex, and left anterior cingulate gyrus. These areas were not activated in a contrast between passive listening to rhythms and a non-auditory control, indicating their role in the temporal processing that was specific to working memory for rhythm. The contrast between working memory for melody and passive listening to melodies activated mainly a right-hemisphere network of frontal, parietal, and temporal cortices: areas involved in pitch processing and auditory working memory. Overall, these results demonstrate that rhythm and melody have unique neural signatures not only in the early stages of auditory processing, but also at the higher cognitive level of working memory.

Autobiographical memories of anger in violent and non-violent individuals: a script-driven imagery study.

Numerous studies have implicated frontal lobe dysfunction in anger-related impulsive violent behavior; however, few studies have looked at frontal activity during angry states in violent individuals. Using PET and a script-driven imagery paradigm, we report on autobiographical memories of angry vs. neutral memories in violent patients and psychiatric matched controls. Relative to recall of neutral memories, recall of anger-laden memories was associated with an activation of frontal regions among control subjects but not violent subjects. Violent subjects demonstrated relatively greater activations in the left amygdala, pontine, and cerebellar regions compared to control subjects.

Fluorodeoxyglucose positron emission tomography of mild cognitive impairment with clinical follow-up at 3 years.

BACKGROUND: Alzheimer's disease (AD) is the most common dementing illness. Development of effective treatments directed at AD requires an early diagnosis. Mild cognitive impairment (MCI) often heralds AD. Thus, characterizing MCI is fundamental to the early diagnosis of AD. METHODS: 19 MCI patients referred from a memory loss clinic and 27 healthy subjects, all followed up for 3 years. Metabolism scans (MCI minus controls) were compared voxel-wise after anatomic normalization and were examined both visually and with a computerized classifier. RESULTS: Agreement between raters as to whether the individual scans were normal or abnormal was high. Agreement between raters of the eventual clinical diagnosis and baseline metabolic pattern was poor. A computerized classifier was unsuccessful at classifying MCI from normal; however, its performance improved when using only prototypic AD-like MCI scans, indicating the classifier worked well when shared patterns existed in the data. Outcomes on follow-up were nine of 19 AD, five of 19 remained MCI, and five of 19 developed dementias other than AD. Both MCI cases of early Lewy body dementia (LBD) showed an AD-like metabolic pattern. CONCLUSIONS: Visual inspection proved reliable in determining normal from abnormal scans, but it proved unreliable at predicting diagnosis on follow-up. Computerized classification of MCI by using an AD-like metabolic template (such as derived from the averaged MCI images) showed potential to identify patients who will develop AD. However, the metabolic pattern in early LBD did not differ from that in AD.

Aging-Related Hypometabolism in the Anterior Cingulate Cortex of Cognitively Intact, Amyloid-Negative Seniors at Rest Mediates the Relationship between Age and Executive Function but Not Memory.

The anterior cingulate cortex (ACC) shows the most aging-related brain metabolic dysfunction that correlates with decreasing executive processing in otherwise healthy, cognitively intact volunteers. Here, data from ADNI are used to elucidate potential pathophysiological mechanisms involved in cognitive aging, that is, age-related decline in cognitive performance in the absence of known neurodegenerative disease. Amyloid-negative volunteers showed statistically significant mediation of ACC metabolism in the relationship between age and verbal fluency. A nonlinguistic task of executive function, Trails B, showed also negative correlation between performance and age, albeit weaker, but was not significant in the mediation analysis. Recall of story items, minimizing attentional demands compared with learning of word lists, did not correlate with age. ADNI subjects selected for low vascular risks also showed correlation between age and declining ACC metabolism. In the whole-brain amyloid-negative subset, ACC amyloid was not correlated with age. As expected, the metabolism in an arbitrary region such as motor cortex that was not expected to decline with cognitive aging showed no correlation with age or ACC metabolism suggesting regional specificity. These findings motivate the search for the pathophysiology of aging-related ACC dysfunction to prevent, diagnose, and treat the decline in executive function associated with cognitive aging.

A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.

Exposure to Cold Unmasks Potential Biomarkers of Fibromyalgia Syndrome Reflecting Insufficient Sympathetic Responses to Stress.

OBJECTIVES: Fibromyalgia syndrome (FMS) is a chronically painful condition whose symptoms are widely reported to be exacerbated by stress. We hypothesized that female patients with FMS differ from pain-free female controls in their sympathetic responses, a fact that may unmask important biomarkers and factors that contribute to the etiology of FMS. MATERIALS AND METHODS: In a pilot study, blood pressure (BP), skin temperature, thermogenic activity, circulating glucose, and pain sensitivity of 13 individuals with FMS and 11 controls at room temperature (24°C) were compared with that after exposure to cold (19°C). RESULTS: When measured at 24°C, BP, skin temperature, blood glucose, and brown adipose tissue (BAT) activity, measured using F-fluorodeoxyglucose positron-emission tomography/computed tomography, did not differ between controls and individuals with FMS. However, after cold exposure (19°C), BP and BAT activity increased in controls but not in individuals with FMS; skin temperature on the calf and arm decreased in controls more than in individiuals with FMS; and circulating glucose was lower in individiuals with FMS than in controls. Pain sensitivity did not change during the testing interval in response to cold. DISCUSSION: The convergence of the effect of cold on 4 relatively simple measures of thermogenic, cardiovascular, and metabolic activity, each regulated by sympathetic activity, strongly indicate that individuals with FMS have impaired sympathetic responses to stress that are observable and highly significant even when measured in extraordinarily small sample populations. If insufficient sympathetic responses to stress are linked to FMS, stress may unmask and maximize these potential clinical biomarkers of FMS and be related to its etiology.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism.

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

Internet image viewer (iiV).

BACKGROUND: Visualizing 3-dimensional (3-D) datasets is an important part of modern neuroimaging research. Many tools address this problem; however, they often fail to address specific needs and flexibility, such as the ability to work with different data formats, to control how and what data are displayed, to interact with values, and to undo mistakes. RESULTS: iiV, an interactive software program for displaying 3-D brain images, is described. This tool was programmed to solve basic problems in 3-D data visualization. It is written in Java so it is extensible, is platform independent, and can display images within web pages.iiV displays 3-D images as 2-dimensional (2-D) slices with each slice being an independent object with independent features such as location, zoom, colors, labels, etc. Feature manipulation becomes easier by having a full set of editing capabilities including the following: undo or redo changes; drag, copy, delete and paste objects; and save objects with their features to a file for future editing. It can read multiple standard positron emission tomography (PET) and magnetic resonance imaging (MRI) file formats like ECAT, ECAT7, ANALYZE, NIfTI-1 and DICOM. We present sample applications to illustrate some of the features and capabilities. CONCLUSION: iiV is an image display tool with many useful features. It is highly extensible, platform independent, and web-compatible. This report summarizes its features and applications, while illustrating iiV's usefulness to the biomedical imaging community.

Bringing functional brain image analysis to the clinician: initial assessment of an online interactive diagnostic aide.

Image database extensions for functional brain images were assessed by asking clinicians questions about (i) diagnosis confidence level before and after using the software; (ii) expected and unexpected differences between patient and control images; and (iii) an overall rating of the future usefulness of this application in an everyday clinical setting. Examining the difference image of a patient compared to a normative group affects the clinicians' initial diagnosis of the patient in two-thirds of the cases. All three clinicians stated that the interface would be a useful tool when added to the clinical workup of a patient.

Atypical Localization and Dissociation between Glucose Uptake and Amyloid Deposition in Cognitively Normal APOE*E4 Homozygotic Elders Compared with Patients with Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) progresses insidiously over decades. Therefore, study of preclinical AD is critical to identify early pathophysiological changes as potential targets for prevention or treatment. The brain processes at the preclinical stage remain minimally understood. Aside from age, the E4 allele of APOE flags a group at particularly high risk of late-onset AD (LOAD). Studies of these individuals could provide insights about the ontogenesis of AD offering clues for novel treatment strategies. To this end, cognitively normal, APOE*E4 homozygotes from the Alzheimer's Diseases Neuroimaging Research Initiative database (ADNI-LONI) provided fluorodeoxyglucose and amyloid (florbetapir) PET scans (n = 8 and 7, respectively; mean age 76 years). Their scans were compared to those of matched cognitively normal elders who were not E4 carriers. There was dissociation in the distribution between glucose uptake and amyloid deposition in the homozygotes. Peak hypometabolism localized bilaterally along the medial temporal cortex. In contrast, peak amyloid deposition localized principally to the putamen, a finding also seen in preclinical carriers of autosomal dominant AD mutations and preclinical AD associated with Down syndrome. Additional regions of amyloid deposition in homozygotes were medial prefrontal cortices including the anterior cingulate, middle and inferior frontal cortices, and middle and inferior occipital cortices. These findings contrast with those reported for LOAD. These data begin to characterize elders with normal cognition despite high AD risk in comparison to the known phenotypes of patients with LOAD.

Metabotropic glutamate receptor 5 tracer [18F]-FPEB displays increased binding potential in postcentral gyrus and cerebellum of male individuals with autism: a pilot PET study.

BACKGROUND: Autism is a neurodevelopmental disorder that is first manifested during early childhood. Postmortem experiments have identified significantly elevated expression of metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and prefrontal cortex of individuals with autism. METHODS: In the current study we employed the mGluR5 tracer [18F]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]-FPEB) to quantify mGluR5 binding in vivo in adults with autism vs. healthy controls using positron emission tomography (PET). RESULTS: We identified significantly higher [18F]-FPEB binding potential in the postcentral gyrus and cerebellum of individuals with autism. There was a significant negative correlation between age and [18F]-FPEB binding potential in the cerebellum but not in the postcentral gyrus. In the precuneus, [18F]-FPEB binding potential correlated positively with the lethargy subscale score for the Aberrant Behavioral Checklist (ABC). In cerebellum, there were significant negative correlations between [18F]-FPEB binding potential and ABC total score, ABC hyperactivity subscale score, and the ABC inappropriate speech subscale score. CONCLUSIONS: These novel findings demonstrate for the first time that mGluR5 binding is altered in critical brain areas of subjects with autism, suggesting abnormal glutamate signaling in these regions. Finally, the correlations between altered [18F]-FPEB binding potential in the cerebellum and precuneus suggest that some autistic symptoms may be influenced by abnormal glutamate signaling.

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders.

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Automated quantitation of cold-inducible human brown adipose tissue with FDG PET/CT with application to fibromyalgia.

Increasing recognition of the importance of brown adipose tissue (BAT) motivates the development of reproducible and quantitative methods for measuring it. Positron emission tomography (PET)/computerized tomography (CT) with 18F-fluorodeoxyglucose (FDG) has become the principal method to non-invasively detect brown adipose tissue (BAT) in humans. Improvements in quantitation and standardization will drive further clinical application. One disorder hypothesized to involve dysregulation in thermoregulation and the processing of pain involving BAT is fibromyalgia syndrome (FMS). This report describes an approach with additional technical standardization to measure cold-inducible, BAT activity (ci-BAT) semi-quantitatively and reliably with minimal operator intervention with the FDG PET/CT technique. Ci-BAT was measured to test whether FMS patients have decreased BAT activation compared to normal controls. Threshold parameters to optimally separate ci-BAT from non-ci-BAT were developed based on the distribution of the pixel-wise parametric data from each merged PET/CT scan for each study session occurring on different days. BAT activity was the same under warm conditions in both control and FMS subjects attesting to reproducibility and reliability. However, considerable variability arose between groups at cool temperatures consistent with other literature. Increases in ci-BAT activity were significantly less in FMS patients than in controls, as hypothesized. Ci-BAT recruitment can be quantified non-invasively using FDG PET/CT using semi-automated techniques in human subjects across different diagnostic groups or within groups undergoing manipulations of interest.

Double dissociation of exteroceptive and interoceptive feedback systems in the orbital and ventromedial prefrontal cortex of humans.

The primate ventral prefrontal cortex contains two densely interconnected subregions: a lateral/orbital cortex processing primarily sensory/exteroceptive information, and a ventromedial cortex processing primarily visceroappetitive/interoceptive information. These regions have major afferents from and efferents to other associative cortices. The organization of these structures leads to an hypothesized role in feedback processing. We use neuroimaging to test this model, defined so far mostly through anatomical studies. Healthy volunteers were trained operantly on a transitive inference task (A>B, B>C ==> A>C) requiring flexible manipulation of feedback to solve. Two groups of subjects learned an arbitrary face hierarchy, one adjacent face pair at a time; each group received either visual/exteroceptive ("XXXX") or visceroappetitive/interoceptive (fruit juice) feedback for correct responses to adjacent face pairs. After task acquisition, the subjects were tested on novel stimulus pairs (i.e., nonadjacent, TEST) derived from the acquired hierarchy. The TEST condition required transitive inference. No feedback was provided during TEST. Brain activity during TEST in the group trained with visual/exteroceptive feedback increased in the orbital prefrontal cortex and decreased in the ventromedial prefrontal cortex. In contrast, brain activity during TEST in the group trained with visceroappetitive/interoceptive feedback decreased in the orbital prefrontal cortex and increased in the ventromedial prefrontal cortex. These results provide functional evidence, consistent with previous anatomical studies, for two major feedback systems in human ventral prefrontal cortex: a lateral system specialized for exteroceptive information and a medial system specialized for interoceptive information. Although highly interconnected, there is a double dissociation of function between these networks in healthy humans.

Neurocognitive dysfunction in antidepressant-free, non-elderly patients with unipolar depression: alerting and covert orienting of visuospatial attention.

BACKGROUND: Cognition is impaired across various domains in young and middle-age adults with unipolar depression. Performance appears in general worse in effortful tasks requiring executive function and attention. Probing specific cognitive operations in depressed patients, such as alerting and covert orienting of visuospatial attention, can better define and characterize the pathophysiology. METHODS: Nine antidepressant-free, clinically depressed patients and fourteen age-matched healthy subjects performed a Posner task with components of phasic alerting and covert orienting of visuospatial attention. Reaction times were analyzed by repeated-measures ANOVA with DIAGNOSIS as the between-group measure. Visual field (FIELD), stimulus onset asynchrony (SOA), and orienting CUE condition were within-subject, repeated measures. RESULTS: ANOVA showed intact attentional orienting in both groups. There were no FIELD differences across groups nor main effects of DIAGNOSIS. Interactions of DIAGNOSIS with SOA and DIAGNOSIS with CUE condition identified a phasic alerting deficit in the depressed patients. There were no significant effects of time-on-task, suggesting adequate vigilance or sustained attention in both groups. Plotting depressed versus control subjects' reaction time for each task condition (Brinley plot) showed linearity with a slope of 1.6 (i.e., patients were 1.6-fold slower) and a correlation coefficient of 0.98 (accounting for 96% of the overall variance). LIMITATIONS: This study contains a small sample with potential for Type II error. The study addressed depression at the syndrome level. Depressed patients selected on particular symptom dimensions (e.g., anxiety, psychomotor retardation, etc.) could reveal abnormalities in hemisphere asymmetries that were not observed here. CONCLUSIONS: These data highlight that global slowing is a major cognitive deficit in depression and arises across levels of difficulty. Putative specific deficits in depression need adjustment for the large effects of global slowing which can mimic selective impairments in more effortful task conditions.