Cerebello-Thalamo-Cortical Hyperconnectivity Classifies Patients and Predicts Long-Term Treatment Outcome in First-Episode Schizophrenia.

It has previously been shown that cerebello-thalamo-cortical (CTC) hyperconnectivity is likely a state-independent neural signature for psychosis. However, the potential clinical utility of this change has not yet been evaluated. Here, using fMRI and clinical data acquired from 214 untreated first-episode patients with schizophrenia (62 of whom were clinically followed-up at least once at the 12th and 24th months after treatment initiation) and 179 healthy controls, we investigated whether CTC hyperconnectivity would serve as an individualized biomarker for diagnostic classification and prediction of long-term treatment outcome. Cross-validated LASSO regression was conducted to estimate the accuracy of baseline CTC connectivity for patient-control classification, with the generalizability of classification performance tested in an independent sample including 42 untreated first-episode patients and 65 controls. Associations between baseline CTC connectivity and clinical outcomes were evaluated using linear mixed model and leave-one-out cross validation. We found significantly increased baseline CTC connectivity in patients (P = .01), which remained stable after treatment. Measures of CTC connectivity discriminated patients from controls with moderate classification accuracy (AUC = 0.68, P < .001), and the classification model had good generalizability in the independent sample (AUC = 0.70, P < .001). Higher CTC connectivity at baseline significantly predicted poorer long-term symptom reduction in negative symptoms (R = 0.31, P = .01) but not positive or general symptoms. These findings provide initial evidence for the putative "CTC hyperconnectivity" anomaly as an individualized diagnostic and prognostic biomarker for schizophrenia, and highlight the potential of this measure in precision psychiatry.

A preliminary study of the effects of mindfulness-based cognitive therapy on structural brain networks in mood-dysregulated youth with a familial risk for bipolar disorder.

BACKGROUND: Mindfulness-based cognitive therapy for children (MBCT-C), as a psychotherapeutic intervention, has been shown to be effective for treating mood dysregulation (MD). While previous neuroimaging studies of MD have reported both pre-treatment structural and functional alterations, the effects of MBCT-C on brain morphological network organisation has not been investigated. METHODS: We investigated brain morphological network organisation in 10 mood-dysregulated youth with familial risk for bipolar disorder and 15 matched healthy comparison youth (HC). Effects of 12 weeks of MBCT-C were examined in the mood-dysregulated youth. Topological properties of brain networks used for analyses were constructed based on morphological similarities in regional grey matter using a graph-theory approach using MRI data. RESULTS: At baseline, compared with the HC group, the mood-dysregulated group exhibited increased global efficiency (Eglob ), decreased path length (Lp ), and abnormal nodal properties, mainly in the limbic system. Right temporal pole alterations at baseline predicted change in Child and Adolescent Mindfulness Measure scores after treatment. The mood-dysregulated group showed significant decreases in both the Eglob and Lp metrics after MBCT-C, suggesting an improved capacity for optimal information processing. Changes in Lp were correlated with changes in Emotion Regulation Checklist scores. Our results show significant topological alterations in the mood-dysregulated group as compared to controls at baseline. After MBCT-C, disrupted topological properties in the mood-dysregulated group were significantly reduced. CONCLUSION: MBCT-C may facilitate clinically meaningful changes in the brain structural network in mood-dysregulated individuals.

Grey matter connectome abnormalities and age-related effects in antipsychotic-naive schizophrenia.

BACKGROUND: Convergent evidence is increasing to indicate progressive brain abnormalities in schizophrenia. Knowing the brain network features over the illness course in schizophrenia, independent of effects of antipsychotic medications, would extend our sight on this question. METHODS: We recruited 237 antipsychotic-naive patients with schizophrenia range from 16 to 73 years old, and 254 healthy controls. High-resolution T1 weighted images were obtained with a 3.0T MR scanner. Grey matter networks were constructed individually based on the similarities of regional grey matter measurements. Network metrics were compared between patient groups and healthy controls, and regression analyses with age were conducted to determine potential differential rate of age-related changes between them. FINDINGS: Nodal centrality abnormalities were observed in patients with untreated schizophrenia, particularly in the central executive, default mode and salience networks. Accelerated age-related declines and illness duration-related declines were observed in global assortativity, and in nodal metrics of left superior temporal pole in schizophrenia patients. Although no significant intergroup differences in age-related regression were observed, the pattern of network metric alternation of left thalamus indicated higher nodal properties in early course patients, which decreased in long-term ill patients. INTERPRETATIONS: Global and nodal alterations in the grey matter connectome related to age and duration of illness in antipsychotic-naive patients, indicating potentially progressive network organizations mainly involving temporal regions and thalamus in schizophrenia independent from medication effects. FUNDING: The National Natural Science Foundation of China, Sichuan Science and Technology Program, the Fundamental Research Funds for the Central Universities, Post-Doctor Research Project, West China Hospital, Sichuan University , the Science and Technology Project of the Health Planning Committee of Sichuan, Postdoctoral Interdisciplinary Research Project of Sichuan University and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Network-level functional topological changes after mindfulness-based cognitive therapy in mood dysregulated adolescents at familial risk for bipolar disorder: a pilot study.

BACKGROUND: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. METHODS: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. RESULTS: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. CONCLUSIONS: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits.

Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances.

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.

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome.

BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.

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.

Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.

BACKGROUND: The neurobiology of suicide is largely unknown. Studies of white matter tracts in patients with a history of suicidal behaviour have shown alteration in the left anterior limb of the internal capsule (ALIC). Our aim was to determine whether particular target fields of fibre projections through the ALIC are affected in depressed patients who recently attempted suicide. METHODS: We studied patients with major depressive disorder (MDD) with and without a history of suicide attempts and healthy controls using diffusion tensor imaging (DTI) and deterministic tractography to generate fibre tract maps for each participant. Tract voxels were coded as being unique to the left ALIC. We compared the mean percentage of fibres projecting to relevant brain regions in the 3 groups using analysis of covariance. RESULTS: We included 63 patients with MDD (23 with and 40 without a history of suicide attempts) and 46 controls in our study. Both groups of depressed patients had reduced fibre projections through the ALIC to the left medial frontal cortex, orbitofrontal cortex and thalamus. Those with a history of suicide attempts had greater abnormalities than those without suicide attempts in the left orbitofrontal cortex and thalamus. LIMITATIONS: Diffusion tensor imaging deterministic tracking is unable to distinguish between afferent and efferent pathways, limiting our ability to distinguish the directionality of altered fibre tracts. CONCLUSION: Frontothalamic loops passing through the ALIC are abnormal in patients with depression and significantly more abnormal in depressed patients with a history of suicide attempts than in those without a history of suicide attempts. Abnormal projections to the orbitofrontal cortex and thalamus may disrupt affective and cognitive functions to confer a heightened vulnerability for suicidal behaviour.

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.

Microstructural abnormalities of white matter differentiate pediatric and adult-onset bipolar disorder.

OBJECTIVES: White-matter microstructure, known to undergo significant developmental transformation, is abnormal in bipolar disorder (BD). Available evidence suggests that white-matter deviation may be more pronounced in pediatric than adult-onset BD. The present study aimed to examine how white-matter microstructure deviates from a typical maturational trajectory in BD. METHODS: Fractional anisotropy (FA) was measured in 35 individuals presenting with first episode BD (type I) and 46 healthy controls (HC) (aged 9-42) using diffusion tensor imaging (DTI). Patients were medication free and close to illness onset at the time of the DTI scans. Tract-based spatial statistics were used to examine the center of white-matter tracts, and FA was extracted from nine tracts of interest. Axial, radial, and mean diffusivity were examined in post-hoc analyses. RESULTS: The left anterior limb of the internal capsule (ALIC) showed significantly lower FA in pediatric than adult-onset BD. The lower FA in BD was due primarily to greater radial, rather than decreased axial, diffusivity. CONCLUSIONS: The ALIC connects the frontal lobes with archistriatum, thalamus, and medial temporal regions, and alteration in these pathways may contribute to mood dysregulation in BD. Abnormalities in this pathway appear to be associated with an earlier onset of illness and thus may reflect a greater susceptibility to illness.

Neural activations during auditory oddball processing discriminating schizophrenia and psychotic bipolar disorder.

BACKGROUND: Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ) but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain, given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatiotemporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders. METHODS: Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multisensor electroencephalography. Principal components analysis was used to reduce multisensor data before evaluating group differences on voltage and frequency of neural responses over time. RESULTS: Linear discriminant analysis revealed five variables that best differentiated groups: 1) late beta activity to standard stimuli; 2) late beta/gamma activity to targets discriminated BPP from other groups; 3) midlatency theta/alpha activity to standards; 4) target-related voltage at the late N2 response discriminated both psychosis groups from H; and 5) target-related voltage during early N2 discriminated BPP from H. CONCLUSIONS: Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.

Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study.

OBJECTIVE: The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD). METHOD: This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 ± 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 ± 2.8 years) were also scanned twice. RESULTS: In post hoc analyses on the significant interaction in a 3×2×2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings. CONCLUSIONS: When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D2) receptor-rich ventral striatum. Clinical trial registration information-Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202.

Spatiotemporal and frequency domain analysis of auditory paired stimuli processing in schizophrenia and bipolar disorder with psychosis.

Individuals with schizophrenia (SZ) or bipolar disorder with psychosis (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.

Atypical involvement of frontostriatal systems during sensorimotor control in autism.

Autism is a neurodevelopmental disorder involving dysmaturation of widely distributed brain systems. Accordingly, behaviors that depend on distributed systems, such as higher level cognition and sensorimotor control, are compromised in the disorder. The current study investigated alterations in neural systems underlying sensorimotor disturbances in autism. An fMRI investigation was conducted using saccadic and pursuit eye movement paradigms with 13 high functioning individuals with autism and 14 age- and IQ-matched typically developing individuals. Individuals with autism had reduced activation in cortical eye fields and cerebellar hemispheres during both eye movement tasks. When executing visually guided saccades, individuals with autism had greater activation bilaterally in a frontostriatal circuit including dorsolateral prefrontal cortex, caudate nucleus, medial thalamus, anterior and posterior cingulate cortex, and right dentate nucleus. The increased activation in prefrontal-striatal-thalamocortical circuitry during visually guided saccades indicates that systems typically dedicated to cognitive control may need to compensate for disturbances in lower-level sensorimotor systems. Reduced activation throughout visual sensorimotor systems may contribute to saccadic and pursuit disturbances that have been reported in autism. These findings document that neurodevelopmental disturbances in autism affect widely distributed brain systems beyond those mediating language and social cognition.

Reduced N-acetyl-aspartate levels in schizophrenia patients with a younger onset age: a single-voxel 1H spectroscopy study.

Schizophrenia is widely considered a neurodevelopmental disorder. The timing of psychosis onset may determine the degree of functional and biological deficits. In this study, the association between age of onset of psychosis and in vivo biochemical levels was assessed in first-episode, antipsychotic-naive (FEAN) schizophrenia subjects. We hypothesized greater biochemical deficits in the younger-onset FEAN subjects. In vivo, (1)H spectroscopy measurements of the left dorsolateral prefrontal cortex (DLPFC) were conducted on FEAN subjects (15 schizophrenia and 3 schizoaffective subjects) and healthy comparison subjects of comparable age and gender distribution (N=61). N-acetyl-aspartate was significantly lower in the left DLPFC of FEAN subjects as compared to healthy comparison subjects. However, there was a significant subject group-by-age interaction for N-acetyl-aspartate. Early-onset FEAN subjects showed lower N-acetyl-aspartate levels compared to the younger healthy comparison subjects, while adult-onset FEAN and older healthy comparison subjects did not differ. The lower N-acetyl-aspartate levels in the DLPFC of early-onset subjects suggest a reduction in functioning neurons or specifically a reduction in the proliferation of dendrites and synaptic connections, which is not apparent in the adult-onset schizophrenia subjects.

Functional neuroanatomy of anticipatory behavior: dissociation between sensory-driven and memory-driven systems.

The ability to anticipate predictable stimuli allows faster responses. The predictive saccade (PRED) task has been shown to quickly induce such anticipatory behavior in humans. In a PRED task subjects track a visual target jumping back and forth between fixed positions at a fixed time interval. During this task, saccade latencies drop from approximately 200 ms to <80 ms as subjects anticipate target appearance. This change in saccade latency indicates that subjects' behavior shifts from being sensory driven to being memory driven. We conducted functional magnetic resonance imaging studies with 10 healthy adults performing the PRED task using a standard block design. We compared the PRED task with a visually guided saccade (VGS) task using unpredictable targets matched for number, direction and amplitude of required saccades. Our results show greater activation during the PRED task in the prefrontal, pre-supplementary motor and anterior cingulate cortices, hippocampus, mediodorsal thalamus, striatum and cerebellum. The VGS task elicited greater activation in the cortical eye fields and occipital cortex. These results demonstrate the important dissociation between sensory and predictive neural control of similar saccadic eye movements. Anticipatory behavior induced by the PRED task required less sensory-related processing activity and was subserved by a distributed cortico-subcortical memory system including prefronto-striatal circuitry.