Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program.

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study.

Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.

Differential modulation of global and local neural oscillations in REM sleep by homeostatic sleep regulation.

Homeostatic rebound in rapid eye movement (REM) sleep normally occurs after acute sleep deprivation, but REM sleep rebound settles on a persistently elevated level despite continued accumulation of REM sleep debt during chronic sleep restriction (CSR). Using high-density EEG in mice, we studied how this pattern of global regulation is implemented in cortical regions with different functions and network architectures. We found that across all areas, slow oscillations repeated the behavioral pattern of persistent enhancement during CSR, whereas high-frequency oscillations showed progressive increases. This pattern followed a common rule despite marked topographic differences. The findings suggest that REM sleep slow oscillations may translate top-down homeostatic control to widely separated brain regions whereas fast oscillations synchronizing local neuronal ensembles escape this global command. These patterns of EEG oscillation changes are interpreted to reconcile two prevailing theories of the function of sleep, synaptic homeostasis and sleep dependent memory consolidation.

Control of sleep and wakefulness.

This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

Prediction of psychosis in prodrome: development and validation of a simple, personalized risk calculator.

BACKGROUND: This study aim to derive and validate a simple and well-performing risk calculator (RC) for predicting psychosis in individual patients at clinical high risk (CHR). METHODS: From the ongoing ShangHai-At-Risk-for-Psychosis (SHARP) program, 417 CHR cases were identified based on the Structured Interview for Prodromal Symptoms (SIPS), of whom 349 had at least 1-year follow-up assessment. Of these 349 cases, 83 converted to psychosis. Logistic regression was used to build a multivariate model to predict conversion. The area under the receiver operating characteristic (ROC) curve (AUC) was used to test the effectiveness of the SIPS-RC. Second, an independent sample of 100 CHR subjects was recruited based on an identical baseline and follow-up procedures to validate the performance of the SIPS-RC. RESULTS: Four predictors (each based on a subset of SIPS-based items) were used to construct the SIPS-RC: (1) functional decline; (2) positive symptoms (unusual thoughts, suspiciousness); (3) negative symptoms (social anhedonia, expression of emotion, ideational richness); and (4) general symptoms (dysphoric mood). The SIPS-RC showed moderate discrimination of subsequent transition to psychosis with an AUC of 0.744 (p < 0.001). A risk estimate of 25% or higher had around 75% accuracy for predicting psychosis. The personalized risk generated by the SIPS-RC provided a solid estimate of conversion outcomes in the independent validation sample, with an AUC of 0.804 [95% confidence interval (CI) 0.662-0.951]. CONCLUSION: The SIPS-RC, which is simple and easy to use, can perform in the same manner as the NAPLS-2 RC in the Chinese clinical population. Such a tool may be used by clinicians to counsel appropriately their patients about clinical monitor v. potential treatment options.

A comparison of neurocognition and functioning in first episode psychosis populations: do research samples reflect the real world?

PURPOSE: The current study evaluates the demographic, clinical, and neurocognitive characteristics of a recruited FEP research sample, a research control group, and a FEP clinic sample that were assessed and treated within the same center and time period. METHODS: This study utilized data collected through an observational study and a retrospective chart review. Samples were ascertained in the Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults study and the Prevention and Recovery in Early Psychosis clinic. FEP clinic patients (n = 77), FEP research participants (n = 44), and age-matched controls (n = 38) were assessed using the MATRICS consensus cognitive battery and global functioning social and role scales. Between-group differences were assessed via one-way ANOVA and Chi-square analyses. RESULTS: No significant differences were observed between groups with regard to age and gender. The FEP research sample had a higher proportion of white participants, better social and role functioning, and better neurocognitive performance when compared with the FEP clinical population. The clinic sample also had more diagnostic variability and higher prevalence of substance use disorders relative to the FEP research sample. CONCLUSIONS: Researchers should be aware of how study design and recruitment practices may impact the representativeness of samples, with particular concern for equal representation of racial minorities and patients with more severe illness. Studies should be designed to minimize burden to promote a wider range of participation.

Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations.

Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. SIGNIFICANCE STATEMENT: Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior.

The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide.

Both sleep loss and pathogens can enhance brain inflammation, sleep, and sleep intensity as indicated by electroencephalogram delta (δ) power. The pro-inflammatory cytokine interleukin-1 beta (IL-1ß) is increased in the cortex after sleep deprivation (SD) and in response to the Gram-negative bacterial cell-wall component lipopolysaccharide (LPS), although the exact mechanisms governing these effects are unknown. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome protein complex forms in response to changes in the local environment and, in turn, activates caspase-1 to convert IL-1ß into its active form. SD enhances the cortical expression of the somnogenic cytokine IL-1ß, although the underlying mechanism is, as yet, unidentified. Using NLRP3-gene knockout (KO) mice, we provide evidence that NLRP3 inflammasome activation is a crucial mechanism for the downstream pathway leading to increased IL-1ß-enhanced sleep. NLRP3 KO mice exhibited reduced non-rapid eye movement (NREM) sleep during the light period. We also found that sleep amount and intensity (δ activity) were drastically attenuated in NLRP3 KO mice following SD (homeostatic sleep response), as well as after LPS administration, although they were enhanced by central administration of IL-1ß. NLRP3, ASC, and IL1ß mRNA, IL-1ß protein, and caspase-1 activity were greater in the somatosensory cortex at the end of the wake-active period when sleep propensity was high and after SD in wild-type but not NLRP3 KO mice. Thus, our novel and converging findings suggest that the activation of the NLRP3 inflammasome can modulate sleep induced by both increased wakefulness and a bacterial component in the brain.

Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats.

Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders.

Effects of NRG1 genotypes on orbitofrontal sulcogyral patterns in Japanese patients diagnosed with schizophrenia.

AIM: Numerous reports have described differences in the distribution of orbitofrontal cortex (OFC) sulcogyral patterns between patients with schizophrenia (SZ patients) and healthy controls (HC). Alterations in OFC morphology are also observed in those at high risk for developing SZ and in first-episode SZ, suggesting that genetic associations may be extant in determining OFC sulcogyral patterns. We investigated the association between single nucleotide polymorphisms (SNP) in NRG1 and OFC sulcogyral patterns. METHODS: A total of 59 Japanese patients diagnosed with SZ and 60 HC were scanned on a 1.5-T magnet. Patients were also assessed clinically. OFC sulcogyral patterns were evaluated for each participant, and genotyping was performed for four SNP in NRG1 (SNP8NRG243177, SNP8NRG221533, SNP8NRG241930, and rs1081062). RESULTS: There were significant differences in the distribution of OFC sulcogyral patterns between SZ patients and HC (χ(2) = 6.52, P = 0.038). SZ patients showed an increase in the frequency of Type III expression, which was associated with an earlier age of disease onset (ß = -0.302, F = 4.948, P = 0.030). Although no difference was found in genotype frequencies between SZ patients and HC, an NRG1 SNP, SNP8NRG243177, was associated with Type II expression in SZ patients (ß = 0.237, F = 4.120, P = 0.047). CONCLUSION: Our results suggest that OFC sulcogyral pattern formation in schizophrenia may be associated with NRG1 allele frequency, which is closely related to neurodevelopment.

Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis.

The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex , lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non-rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low-theta power (5-7 Hz), but not high-theta (7-9 Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx ]ex and [AD]ex . Lesions of ChBF cells using IgG 192-saporin prevented increases in [NOx ]ex , [AD]ex and low-theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex . Infusion of NO donor DETA NONOate into the saporin-treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD-induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low-theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP.

Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain.

Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and ß-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26-31% from SR1 to R1). A decrease in ß-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction.

Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia.

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder.

Molecular profiles of pyramidal neurons in the superior temporal cortex in schizophrenia.

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30-100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-ß) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset.

Diffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia in vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic, and immunochemical studies support the involvement of axonal degeneration and neuroinflammation--ubiquitous components of neurodegenerative disorders--as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early diagnosed schizophrenia patients.

Knockdown of orexin type 2 receptor in the lateral pontomesencephalic tegmentum of rats increases REM sleep.

Dysfunction of the orexin/hypocretin neurotransmitter system causes the sleep disorder narcolepsy, characterized by intrusion of rapid eye movement (REM) sleep-like events into normal wakefulness. The sites where orexins act to suppress REM sleep are incompletely understood. Previous studies suggested that the lateral pontomesencephalic tegmentum (lPMT) contains an important REM sleep inhibitory area, and proposed that orexins inhibit REM sleep via orexin type 2 receptors (OxR2) in this region. However, this hypothesis has heretofore not been tested. We thus performed bilateral injection of small interfering RNAs (siRNAs) targeting Ox2R into the lPMT on two consecutive days. This led to a approximately 30% increase of time spent in REM sleep in both the dark and light periods for the first 2 days after injection, with a return to baseline over the next two post-injection days. This increase was mainly due to longer (> 120 s) REM episodes. Cataplexy-like episodes were not observed. The percentage of time spent in wakefulness and non-(N)REM sleep, as well as the power spectral profile of NREM and REM sleep, were unaffected. Control animals injected with scrambled siRNA had no sleep changes post-injection. Quantification of the knockdown revealed that unilateral microinjection of siRNAs targeting OxR2 into the lPMT induced a approximately 40% reduction of OxR2 mRNA 2 days following the injections when compared with the contralateral side receiving control (scrambled) siRNA. Orexin type 1 receptor mRNA level was unaffected. Our results indicate that removal of OxR2 neurotransmission in the lPMT enhances REM sleep by increasing the duration of REM episodes.

Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations.

Impairment of cortical circuit function is increasingly believed to be central to the pathophysiology of schizophrenia (Sz). Such impairments are suggested to result in abnormal gamma band oscillatory activity observed in Sz patients, and likely underlie the psychosis and cognitive deficits linked to this disease. Development of improved therapeutic strategies to enhance functional outcome of Sz patients is contingent upon a detailed understanding of the mechanisms behind cortical circuit development and maintenance. Convergent evidence from both Sz clinical and preclinical studies suggests impaired activity of a particular subclass of interneuron which expresses the calcium binding protein parvalbumin is central to the cortical circuit impairment observed. Here we review our current understanding of the Sz related cortical circuit dysfunction with a particular focus on the role of fast spiking parvalbumin interneurons in both normal cortical circuit activity and in NMDA receptor hypofunction models of the Sz disease state.

Early auditory gamma band response abnormalities in first hospitalized schizophrenia.

BACKGROUND: Abnormalities in coherent cortical circuit functioning, reflected in gamma band activity (to approximately 40 Hz), may be a core deficit in schizophrenia. The early auditory gamma band response (EAGBR) is a neurophysiologically simple probe of circuit functioning in primary auditory cortex. We examined the EAGBR in first hospitalized schizophrenia to assess whether it was reduced at first hospitalization. METHOD: Wavelet evoked power and intertrial phase locking of the EAGBR at Fz to standard tones during an oddball target detection task were examined in 28 first hospitalized schizophrenia patients (10 female) and 44 control subjects (17 female). RESULTS: At first hospitalization EAGBR trial-to-trial phase locking and evoked power were significantly reduced in patients. Although reduced overall in patients, greater total symptoms were significantly associated with greater gamma phase locking and power. Additionally, greater EAGBR power was marginally associated with greater positive factor scores, hallucinations, and thinking disturbance. CONCLUSIONS: Abnormalities of gamma band functioning in local auditory sensory circuits are present in schizophrenia at first hospitalization further evidence that basic sensory processes are impaired in schizophrenia. It remains to be determined whether the EAGBR becomes permanently impaired with disease progression, and if its reduction is specific to schizophrenia.

Longitudinal loss of gray matter volume in patients with first-episode schizophrenia: DARTEL automated analysis and ROI validation.

Region of Interest (ROI) longitudinal studies have detected progressive gray matter (GM) volume reductions in patients with first-episode schizophrenia (FESZ). However, there are only a few longitudinal voxel-based morphometry (VBM) studies, and these have been limited in ability to detect relationships between volume loss and symptoms, perhaps because of methodologic issues. Nor have previous studies compared and validated VBM results with manual Region of Interest (ROI) analysis. In the present VBM study, high-dimensional warping and individualized baseline-rescan templates were used to evaluate longitudinal volume changes within subjects and compared with longitudinal manual ROI analysis on the same subjects. VBM evaluated thirty-three FESZ and thirty-six matched healthy control subjects (HC) at baseline (cross-sectionally) and longitudinally evaluated 21 FESZ and 23 HC after an average of 1.5 years from baseline scans. Correlation analyses detected the relationship between changes in regional GM volumes in FESZ and clinical symptoms derived from the Brief Psychiatric Rating Scale, as well as cognitive function as assessed by the Mini-Mental State Examination. At baseline, patients with FESZ had significantly smaller GM volume compared to HC in some regions including the left superior temporal gyrus (STG). On rescan after 1.5 years, patients showed significant GM volume reductions compared with HC in the left STG including Heschl's gyrus, and in widespread brain neocortical regions of frontal, parietal, and limbic regions including the cingulate gyrus. FESZ showed an association of positive symptoms and volume loss in temporal (especially STG) and frontal regions, and negative symptoms and volume loss in STG and frontal regions. Worse cognitive function was linked to widespread volume reduction, in frontal, temporal and parietal regions. The validation VBM analyses showed results similar to our previous ROI findings for STG and cingulate gyrus. We conclude FESZ show widespread, progressive GM volume reductions in many brain regions. Importantly, these reductions are directly associated with a worse clinical course. Congruence with ROI analyses suggests the promise of this longitudinal VBM methodology.