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Research indicates that high utilizers of the health care system are more likely to have mental illness, to be from socially disadvantaged groups, and to have limited access to community-based services. In this retrospective study, three definitions of high utilization were examined: (1) across time: non-high utilization versus high-utilization, (2) single year versus multi-year, and (3) year-to-year. Univariate logistic regression models were fit to a set of 20 theory-selected predictors of high utilization. An optimal multiple predictor model was then derived via penalized multiple logistic regression (via elastic net, a machine learning algorithm). Three factors were identified in the optimized model as increasing the likelihood of high utilization: having a diagnosis of schizophrenia, having a co-occurring personality disorder diagnosis, and having less than a high school education. Given the complex needs of psychiatric high utilizers, innovative approaches should be considered to improve patient outcomes and reduce costly psychiatric hospitalizations.

Working memory dysfunction may be central to neurocognitive deficits in schizophrenia. Maintenance of visual information in working memory, or visual short-term memory (vSTM), is linked to general cognitive dysfunction and predicts functional outcome. Lateralized change-detection tasks afford investigation of the contralateral delay activity (CDA), a useful tool for investigating vSTM dysfunction. Previous work suggests "hyperfocusing" of attention in schizophrenia, such that CDA is increased when a single item is maintained in vSTM but reduced for multiple items. If observed early in the disease, vSTM dysfunction may be a key feature of schizophrenia or target for intervention. We investigated CDA during lateralized vSTM of one versus three items using sensor-level electroencephalography and source-level magnetoencephalography in 26 individuals at their first episode of schizophrenia-spectrum psychosis (FESz) and 26 matched healthy controls. FESz were unable to modulate CDA with increased memory load - high-load CDA was reduced and low-load CDA was increased compared to controls. Further, sources of CDA in posterior parietal cortex were reduced in FESz and indices of working memory were correlated with neurocognitive deficits and symptom severity. These results support working memory maintenance dysfunction as a central and early component to the disorder. Targeted intervention focusing on vSTM deficits may be warranted to alleviate downstream effects of this disability.

Objective Emergency department (ED)–initiated buprenorphine may prevent overdose. Microdosing is a novel approach that does not require withdrawal, which can be a barrier to standard inductions. We aimed to evaluate the feasibility of an ED‐initiated buprenorphine/naloxone program providing standard‐dosing and microdosing take‐home packages and of randomizing patients to either intervention. Methods We broadly screened patients ≥18 years old for opioid use disorder at a large, urban ED. In a first phase, we provided consecutive patients with 3‐day standard‐dosing packages, and then we provided a subsequent group with 6‐day microdosing packages. In a second phase, we randomized patients to standard dosing or microdosing. We attempted 7‐day telephone follow‐ups and 30‐day in‐person community follow‐ups. The primary feasibility outcome was number of patients enrolled and accepting randomization. Secondary outcomes were numbers screened, follow‐up rates, and 30‐day opioid agonist therapy retention. Results We screened 3954 ED patients and identified 94 with opioid use disorders. Of the patients, 26 (27.7%) declined participation: 10 identified a negative prior experience with buprenorphine/naloxone as the reason, 5 specifically cited precipitated withdrawal, and none cited randomization. We enrolled 68 patients. A total of 14 left the ED against medical advice, 8 were excluded post‐enrollment, 21 received standard dosing, and 25 received microdosing. The 7‐day and 30‐day follow‐up rates were 9/46 (19.6%) and 15/46 (32.6%), respectively. At least 5/21 (23.8%) provided standard dosing and 8/25 (32.0%) provided microdosing remained on opioid agonist therapy at 30 days. Conclusions ED‐initiated take‐home standard‐dosing and microdosing buprenorphine/naloxone programs are feasible, and a randomized controlled trial would be acceptable to our target population.

Memory dysfunction and associated hippocampal disturbances play crucial roles in cognitive impairment of schizophrenia. To examine the relationships between cognitive function and the hippocampal subfields (HSs) in first-episode never-treated (FENT) schizophrenia patients, the HSs were segmented in 39 FENT patients and 30 healthy controls using a state-of the-art automated algorithm. We found no significant differences in any HSs between the patients and controls. However, multivariate regression analysis showed that the left cornu ammonis 1 (CA1), left hippocampal tail, left presubiculum, and right molecular layer contributed 40% to the variance of the PANSS negative symptom score. After adjusting for sex, age, education, and intracranial volume, the partial correlation analysis showed that the volumes of left CA1, CA3, CA4, molecular layer, granule cell layer and both left and right subiculum were negatively correlated with the MATRICS consensus cognitive battery (MCCB) Hopkins Verbal Learning Test (HVLT). Multiple regression analysis showed that the left CA1 and CA3 hippocampal abnormalities contributed 66% to the variance of the HVLT. Our results suggest no detectable HS deficits were found in FENT schizophrenia patients. However, the HSs may be involved in the symptoms and cognitive deficits of schizophrenia patients in the early phase of their illness.

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that can be chronic and debilitating if not properly treated. Current first-line treatments for OCD include cognitive-behavioral therapy with exposure and response prevention and serotonin uptake inhibitor medications; however, these therapies are not effective for all individuals.Deep transcranial magnetic stimulation (dTMS) has been hypothesized to be an effective alternative for individuals with treatment-resistant OCD. dTMS has thought to be favorable due to its low side effect profile and its minimally invasive nature.This review evaluates the current research on effectiveness of dTMS therapy for individuals with treatment-resistant OCD. This review also investigates shortcomings in current dTMS research and the hypothesized future of dTMS therapy.

BACKGROUND Suboptimal medication adherence is a significant problem for patients with serious mental illness (SMI). Measuring medication adherence through subjective and objective measures can be challenging, time consuming and inaccurate. OBJECTIVE We evaluated a digital medicine system (DMS) compared to treatment as usual (TAU) on adherence to oral aripiprazole and patient and provider perspectives on the feasibility and acceptability of a DMS. METHODS This open-label, 2-site, provider-randomized trial assessed aripiprazole refill adherence in Veterans with schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder. We randomized 26 providers such that their patients either received TAU or DMS for a period of 90 days. Semi-structured interviews with patients and providers were used to examine feasibility and acceptability of using the DMS. RESULTS We enrolled 46 patients across 2 Veterans Affairs (VA) sites: (21 in DMS and 25 in TAU). There was no difference in medication refill over 3 and 6 months, respectively (82% and 75% DMS vs. 86% and 82% TAU). The DMS arm had 85% days covered during the period they were engaged with the DMS (144 days on average). Interviews with patients (n=14) and providers (n=5) elicited themes salient to using the DMS. Patient themes included: pre-enrollment adherence strategies and interest in the DMS, positive impact on medication adherence, system usability challenges, support needs, and suggested design/functionality improvements. Provider themes included: concerns for patient medication adherence and interest in the DMS, concerns with the DMS, DMS dashboard usability, challenges of the DMS, and suggestions to increase provider use. CONCLUSIONS There was no observed difference in refill rates. Among those who engaged in the DMS arm, refill rates were relatively high (85%). The qualitative analyses highlighted areas for further refinement of the DMS. CLINICALTRIAL NCT03881449

Background Suboptimal medication adherence is a significant problem for patients with serious mental illness. Measuring medication adherence through subjective and objective measures can be challenging, time-consuming, and inaccurate. Objective The primary purpose of this feasibility and acceptability study was to evaluate the impact of a digital medicine system (DMS) among Veterans (patients) with serious mental illness as compared with treatment as usual (TAU) on medication adherence. Methods This open-label, 2-site, provider-randomized trial assessed aripiprazole refill adherence in Veterans with schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder. We randomized 26 providers such that their patients either received TAU or DMS for a period of 90 days. Semistructured interviews with patients and providers were used to examine the feasibility and acceptability of using the DMS. Results We enrolled 46 patients across 2 Veterans Health Administration sites: 21 (46%) in DMS and 25 (54%) in TAU. There was no difference in the proportion of days covered by medication refill over 3 and 6 months (0.82, SD 0.24 and 0.75, SD 0.26 in DMS vs 0.86, SD 0.19 and 0.82, SD 0.21 in TAU, respectively). The DMS arm had 0.85 (SD 0.20) proportion of days covered during the period they were engaged with the DMS (mean 144, SD 100 days). Interviews with patients (n=14) and providers (n=5) elicited themes salient to using the DMS. Patient findings described the positive impact of the DMS on medication adherence, challenges with the DMS patch connectivity and skin irritation, and challenges with the DMS app that affected overall use. Providers described an overall interest in using a DMS as an objective measure to support medication adherence in their patients. However, providers described challenges with the DMS dashboard and integrating DMS data into their workflow, which decreased the usability of the DMS for providers. Conclusions There was no observed difference in refill rates. Among those who engaged in the DMS arm, the proportion of days covered by refills were relatively high (mean 0.85, SD 0.20). The qualitative analyses highlighted areas for further refinement of the DMS. Trial Registration ClinicalTrials.gov NCT03881449; https://clinicaltrials.gov/ct2/show/NCT03881449

Clinic-based transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to improve pain. However, no published studies have reported using home-based self-administered tDCS in older adults with knee osteoarthritis (OA). The present study aimed to evaluate the preliminary efficacy and feasibility of home-based self-administered tDCS with real-time remote supervision on clinical pain, anxiety, depression, and sleep disturbances in older adults with knee OA. Twenty 50- to 85-year-old community-dwelling participants with knee OA received 10 daily home-based sessions of 2 mA tDCS for 20 min with real-time remote supervision. We measured clinical pain severity via the Visual Analog Scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Short-Form McGill Pain Questionnaire. We assessed anxiety, depression, and sleep disturbances using the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety-short form, depression-short form, and sleep disturbance-short form, respectively. All 20 participants completed all 10 home-based tDCS sessions without serious adverse effects. Both clinical pain severity and sleep disturbances were improved after completion of the 10 tDCS sessions. Anxiety and depression scores were not significantly improved. We demonstrated that home-based self-administered tDCS with real-time remote supervision was feasible and beneficial in alleviating clinical pain in older adults with knee OA. These findings support future studies with larger samples and longer-term follow-up evaluations.

This paper presents the novel study of deep brain stimulation using electromagnetic waves. Using giga-hertz electric fields, we can manipulate both amplitudes and phases to achieve focal stimulation at target regions inside the brain tissue. However, the issue with this approach would be that neurons have priorly been shown to respond to lower frequency electric fields (~1kHz). To overcome this issue, similar to the recently proposed temporal interference stimulation for electric currents, we propose using two giga-hertz electromagnetic waves differing from each other by a small frequency offset to potentially modulate neurons for non-invasive deep brain stimulation purposes. Moreover, leveraging the advances in antenna technology, we can create miniature antenna arrays at giga-hertz that can be endocranially implanted to allow for continuous operation, which can also help mitigate signal attenuation. To achieve high focality, we then propose an optimization framework that optimizes the antenna array phases and amplitudes to achieve focal stimulation at multiple target regions inside the brain tissue without moving the antenna arrays. We test the efficacy of our proposed method via Finite Element Method simulations on four realistic 2D human brain phantoms. Our results show that with endocranially implanted array size of mean 4.6cm consisting of point source antenna array elements, a focality of mean 3cm can be achieved at targets deep inside the brain tissue.

Retrograde BMP signaling and canonical pMad/Medea-mediated transcription regulate diverse target genes across subsets ofDrosophilaefferent neurons, to differentiate neuropeptidergic neurons and promote motor neuron terminal maturation. How a common BMP signal regulates diverse target genes across many neuronal subsets remains largely unresolved, although available evidence implicates subset-specific transcription factor codes rather than differences in BMP signaling. Here we examine thecis-regulatory mechanisms restricting BMP-inducedFMRFaneuropeptide expression to Tv4-neurons. We find that pMad/Medea bind at an atypical, low affinity motif in theFMRFaenhancer. Converting this motif to high affinity caused ectopic enhancer activity and eliminated Tv4-neuron expression. In silico searches identified additional motif instances functional in other efferent neurons, implicating broader functions for this motif in BMP-dependent enhancer activity. Thus, differential interpretation of a common BMP signal, conferred by low affinity pMad/Medea binding motifs, can contribute to the specification of BMP target genes in efferent neuron subsets.

BACKGROUND: Knowledge is lacking regarding deficits in selective attention and their underlying biological mechanisms during early stages of schizophrenia. The present study examined the N2pc, a neurophysiological index of covert spatial attention, and its cortical sources at first psychotic episode in the schizophrenia spectrum (FESz). METHODS: Neurophysiological responses measured simultaneously with magnetoencephalography (MEG) and electroencephalography (EEG) during pop-out and serial search tasks were compared between 32 FESz and 32 matched healthy controls (HC). Mean scalp-recorded N2pc was measured from a cluster of posterior-lateral EEG electrodes. Cortical source-resolved MEG activity contributing to the N2pc signal was derived for the intraparietal sulcus (IPS) and lateral occipital complex (LOC). RESULTS: Group differences in EEG N2pc varied by task demand. FESz exhibited reduced N2pc amplitude during pop-out (p

Background/objectives Micro-induction is a novel buprenorphine induction approach that seeks to avoid withdrawal and minimize precipitated withdrawal, both barriers to standard inductions. We aimed to synthesize evidence on micro-induction effectiveness, and regimens described. Methods We searched scientific databases and grey literature for studies including adolescents or adults with opioid use disorder who received buprenorphine micro-induction. Study selection, data extraction and quality assessments occurred in duplicate. We narratively synthesized results. Results We screened 4,752 citations and included 19 case studies/series and one feasibility study (n = 57 patients; mean age 38 years [SD 12.0]; 57.9% male [33/57]). Studies described 26 regimens; starting and maintenance doses ranged from 0.03 to 1.0 mg, and 8 to 32 mg, respectively. We calculated rate of increase to 8 mg. All patients achieved the desired maintenance dose. Among 54 patients in whom precipitated withdrawal was not reported, mean increases were 1.36 mg/day (SD 0.41). For three patients in whom precipitated withdrawal was specifically reported, mean increase was 1.17 mg/day (SD 0.11). All studies were low quality. Discussion Described regimens are highly variable. Inconsistent reporting, selection bias, and poor quality evidence limit conclusions regarding optimal dosing, and patient characteristics and clinical settings in which micro-induction is likely beneficial. Conclusions This systematic review provides the most up-to-date synthesis on buprenorphine micro-induction regimens. Rigorous studies evaluating effectiveness and safety of micro-induction, and patient and clinical factors influencing its success, are needed.

Cognitive deficits in people with schizophrenia are among the hardest to treat and strongly predict functional outcome. The ability to maintain sensory precepts in memory over a short delay is impacted early in the progression of schizophrenia and has been linked to reliable neurophysiological markers. Yet, little is known about the mechanisms of these deficits. Here, we investigated possible neurophysiological mechanisms of impaired visual short-term memory (vSTM, aka working memory maintenance) in the first-episode schizophrenia spectrum (FESz) using magnetoencephalography (MEG). Twenty-eight FESz and 25 matched controls performed a lateralized change detection task where they were cued to selectively attend and remember colors of circles presented in either the left or right peripheral visual field over a 1 s delay. Contralateral alpha suppression (CAS) during the delay period was used to assess selective attention to cued visual hemifields held in vSTM. Delay-period CAS was compared between FESz and controls and between trials presenting one vs three items per visual hemifield. CAS in dorsal visual cortex was reduced in FESz compared to controls in high-load trials, but not low-load trials. Group differences in CAS were found beginning 100 ms after the disappearance of the memory set, suggesting deficits were not due to the initial deployment of attention to the cued visual hemifield prior to stimulus presentation. CAS was not greater for high-load vs low-load trials in FESz subjects, although this effect was prominent in controls. Further, lateralized gamma (34-40 Hz) power emerged in dorsal visual cortex prior to the onset of CAS in controls but not FESz. Gamma power in this cluster differed between groups at both high and low load. CAS deficits observed in FESz were correlated with change detection accuracy, working memory function, estimated IQ, and negative symptoms. Our results implicate deficits in CAS in trials requiring broad, but not narrow, focus of attention to spatially distributed objects maintained in vSTM in FESz, possibly due to reduced ability to broadly distribute visuospatial attention (alpha) or disruption of object-location binding (gamma) during encoding/consolidation. This early pathophysiology may shed light upon mechanisms of emerging working memory deficits that are intrinsic to schizophrenia.

Low-intensity focused ultrasound (LIFU) has been shown to modulate neural activity. Recent experiments suggest potential applications of LIFU stimulation for treating neuropsychiatric disorders like depression and Alzheimer’s. The modulation effect is usually positively correlated with the ultrasound intensity, and there exists a minimum intensity threshold for the neuromodulation to be effective. Therefore, precise configuring of the ultrasound transducer is required to sonicate the target brain region at the desired intensity with appropriate spatial resolution. In this study, we investigate the optimization of targeting through fine temporal and spatial power delivery control of a phased array of ultrasound elements. A novel metric of the ultrasound neuromodulation resolution is proposed, and an optimization problem is formulated and solved to minimize side effects in the form of off-target region sonications. Simulation results show that our method is able to significantly improve the focusing resolution compared to the benchmark and reduce the volume experiencing possible off-target neuromodulation.

A great deal of research has been performed with the promise of improving such critical cognitive functions as working memory (WM), with transcranial direct current stimulation (tDCS), a well-tolerated, inexpensive, easy-to-use intervention. Under the assumption that by delivering currents through electrodes placed in suitable locations on the scalp, it is possible to increase prefrontal cortex excitability and therefore improve WM. A growing number of studies have led to mixed results, leading to the realization that such oversimplified assumptions need revision. Models spanning currents to behavior have been advocated in order to reconcile and inform neurostimulation investigations. We articulate such multilevel exploration to tDCS/WM by briefly reviewing critical aspects at each level of analysis but focusing on the circuit level and how available biophysical WM models could inform tDCS. Indeed, such models should replace vague reference to cortical excitability changes with relevant tDCS net effects affecting neural computation and behavior in a more predictable manner. We will refer to emerging WM models and explore to what extent the general concept of excitation-inhibition (E/I) balance is a meaningful intermediate level of analysis, its relationship with gamma oscillatory activity, and the extent to which it can index tDCS effects. We will highlight some predictions that appear consistent with empirical evidence - such as non-linearities and trait dependency of effects and possibly a preferential effect on WM control functions - as well as limitations that appear related to the dynamical aspects of coding by persistent activity.

Increased anticholinergic activity resulting from pharmacotherapies used to treat schizophrenia is associated with poorer cognition. However the neural mechanisms underlying this effect are unknown. In this study of 39 early course schizophrenia outpatients, we demonstrate that increased serum anticholinergic activity is associated with reduced activation across the prefrontal cortex, including the dorsolateral, anterior, and medial prefrontal cortices, during two tasks of cognitive control. Lower activation in the dorsolateral and anterior prefrontal cortices mediated the association between increased anticholinergicity and poorer neurocognitive function. Such findings provide preliminary insight into how anticholinergic medications may impact cognition through reduced prefrontal cortical function in schizophrenia.

U.S. Hispanics, now the single largest minority group in the country, face unique mental health disparities. The current study utilizes Andersen's Behavioral Model of Health Service Use to examine ethnic disparities in receiving a schizophrenia or mood disorder diagnosis at psychiatric hospital admission. Our retrospective cohort study examined electronic health record data at an academic safety-net psychiatric hospital for adult patients (n = 5571) admitted between 2010 and 2013. Logistic regression with block-wise entry of predisposing, enabling and need variables was used to examine ethnic disparities in receiving a schizophrenia diagnosis at admission. The block of need factors was the strongest predictor of receiving a schizophrenia diagnosis compared to predisposing and enabling factors. Compared to non-Hispanic whites, Hispanics and African Americans had a greater likelihood of receiving a schizophrenia diagnosis at admission. Additionally, patients diagnosed with schizophrenia had elevated positive and negative symptoms and were more likely to be male, single/unmarried, homeless, high inpatient service utilizers, involuntarily hospitalized, and to exhibit functional impairment at psychiatric hospital admission. To address elevated positive and negative symptoms of schizophrenia, functional impairment, social withdrawal, and high inpatient service utilization, promising psychosocial interventions should be adapted for racial and ethnic minority populations and utilized as an adjuvant to antipsychotic medication.

Young adults experiencing first-episode psychosis have historically been difficult to retain in mental health treatment. Communities across the United States are implementing Coordinated Specialty Care to improve outcomes for individuals experiencing first-episode psychosis. This mixed-methods research study examined the relationship between program services and treatment retention, operationalized as the likelihood of remaining in the program for 9 months or more. In the adjusted analysis, male gender and participation in home-based cognitive behavioral therapy were associated with an increased likelihood of remaining in treatment. The key informant interview findings suggest the shared decision-making process and the breadth, flexibility, and focus on functional recovery of the home-based cognitive behavioral therapy intervention may have positively influenced treatment retention. These findings suggest the use of shared decision-making and improved access to home-based cognitive behavioral therapy for first-episode psychosis patients may improve outcomes for this vulnerable population.

Previous studies consistently showed that IL-3 signaling may be involved in the pathophysiology of schizophrenia. However, investigations of associations between IL-3 and the neurocognitive impairments are lacking, including the study of how this may vary with stage of illness. We recruited 45 first-episode drug-naïve (FE-Sz), 35 chronic medicated schizophrenia (Ch-Sz) and 40 healthy controls (HC) and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-3. Altered serum IL-3 levels were found in both patient groups compared with HC group (both p 0.001). There were significantly lower neurocognitive scores on the RBANS and nearly all of its five subscales, except for Visuospatial/Constructional index in both FE-Sz and Ch-Sz patients vs healthy controls. Moreover, a significant reduction in Immediate memory index (p = 0.021) and a trend-level reduction in RBANS total score (p = 0.094) in Ch-Sz than FE-Sz patients. Interestingly, there was a significant negative correlation between IL-3 and the Immediate memory index only in Ch-Sz patients (p = 0.03). Our findings showed that neurocognitive impairments present in schizophrenia emerge during the first episode with further diminished functioning with disease progression, and IL-3 may be involved in the immediate memory deficits in the chronic phase of schizophrenia.

Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.

Multiple lines of evidence indicate that patients with chronic schizophrenia (SCZ) display executive dysfunction across the illness course. However, the potential molecular pathophysiologic mechanisms remain poorly elucidated. Neurodevelopmental changes caused by alterations of inflammatory mediators and neurotrophins have been shown to occur in the earliest stages of SCZ, and be associated with executive dysfunction (ED) in SCZ. Therefore, the current study was to investigate whether the interplay between BDNF and inflammatory mediators was involved in the disruption of executive function of long-term hospitalized patients with chronic SCZ. Serum cytokines and BDNF levels were measured in 112 long-term hospitalized patients with chronic SCZ and 44 healthy normal controls. Executive functions were assessed by verbal fluency tests (VFT), the Stroop word-color test (Stroop), and the Wisconsin card sorting tests (WCST).The results showed that the patients had higher IL-2, IL-6, IL-8, but lower TNF-α and BDNF compared to control subjects. In the patient group, BDNF was positively associated with IL-2 and IL-8 levels, while lower BDNF levels were correlated with ED measured by VFT and WCST tests. Multiple stepwise regression analyses confirmed that BDNF × IL-8 and BDNF × TNF-α were factors influencing the total score of VFT, while BDNF × IL-8 and BDNF × TNF-α were recognized as influencing factors for WCST scores. Our results suggest complex interactions between BDNF and cytokines were involved in the pathophysiology of executive function impairments in patients with SCZ.

Background Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations. Results We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions. Conclusions These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway.

BackgroundSchizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia.MethodA total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).ResultsOf the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB.ConclusionsIGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Previous work has identified a hierarchical organization of neural oscillations that supports performance of complex cognitive and perceptual tasks, and can be indexed with phase-amplitude coupling (PAC) between low- and high-frequency oscillations. Our aim was to employ enhanced source localization afforded by magnetoencephalography (MEG) to expand on earlier reports of intact auditory cortical PAC in schizophrenia and to investigate how PAC may evolve over the early and chronic phases of the illness. Methods Individuals with early schizophrenia (n=12) (≤5 years of illness duration), chronic schizophrenia (n=16) (>5 years of illness duration) and healthy comparators (n = 17) performed the auditory steady state response (ASSR) to 40, 30, and 20 Hz stimuli during MEG recordings. We estimated amplitude and PAC on the MEG ASSR source localized to the auditory cortices. Results Gamma amplitude during 40-Hz ASSR exhibited a significant group by hemisphere interaction, with both patient groups showing reduced right hemisphere amplitude and no overall lateralization in contrast to the right hemisphere lateralization demonstrated in controls. We found significant PAC in the right auditory cortex during the 40-Hz entrainment condition relative to baseline, however, PAC did not differ significantly between groups. Conclusions In the current study, we demonstrated an apparent sparing of ASSR-related PAC across phases of the illness, in contrast with impaired cortical gamma oscillation amplitudes. The distinction between our PAC and evoked ASSR findings supports the notion of separate but interacting circuits for the generation and maintenance of sensory gamma oscillations. The apparent sparing of PAC in both early and chronic schizophrenia patients could imply that the neuropathology of schizophrenia differentially affects these mechanisms across different stages of the disease. Future studies should investigate the distinction between PAC during passive tasks and more cognitively demanding task such as working memory so that we can begin to understand the influence of schizophrenia neuropathology on the larger framework for modulating neurocomputational capacity.

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression disorder (MDD). ECT can induce neurogenesis and synaptogenesis in hippocampus, which contains distinct subfields, e.g., the cornu ammonis (CA) subfields, a granule cell layer (GCL), a molecular layer (ML), and the subiculum. It is unclear which subfields are affected by ECT and whether we predict the future treatment response to ECT by using volumetric information of hippocampal subfields at baseline? In this study, 24 patients with severe MDD received the ECT and their structural brain images were acquired with magnetic resonance imaging before and after ECT. A state-of-the-art hippocampal segmentation algorithm from Freesurfer 6.0 was used. We found that ECT induced volume increases in CA subfields, GCL, ML and subiculum. We applied a machine learning algorithm to the hippocampal subfield volumes at baseline and were able to predict the change in depressive symptoms (r = 0.81; within remitters, r = 0.93). Receiver operating characteristic analysis also showed robust prediction of remission with an area under the curve of 0.90. Our findings provide evidence for particular hippocampal subfields having specific roles in the response to ECT. We also provide an analytic approach for generating predictions about clinical outcomes for ECT in MDD.

Identifying biomarkers in schizophrenia during the first episode without the confounding effects of treatment has been challenging. Leveraging these biomarkers to establish diagnosis and make individualized predictions of future treatment responses to antipsychotics would be of great value, but there has been limited progress. In this study, by using machine learning algorithms and the functional connections of the superior temporal cortex, we successfully identified the first-episode drug-naive (FEDN) schizophrenia patients (accuracy 78.6%) and predict their responses to antipsychotic treatment (accuracy 82.5%) at an individual level. The functional connections (FC) were derived using the mutual information and the correlations, between the blood-oxygen-level dependent signals of the superior temporal cortex and other cortical regions acquired with the resting-state functional magnetic resonance imaging. We also found that the mutual information and correlation FC was informative in identifying individual FEDN schizophrenia and prediction of treatment response, respectively. The methods and findings in this paper could provide a critical step toward individualized identification and treatment response prediction in first-episode drug-naive schizophrenia, which could complement other biomarkers in the development of precision medicine approaches for this severe mental disorder.

Peripheral and CNS-localized inflammatory processes are hypothesized to contribute to the complex pathophysiology of schizophrenia. Elevated levels of the acute phase reactant C-reactive protein (CRP) have been observed in schizophrenia, yet relatively few studies have investigated the association between this inflammatory biomarker and psychotic symptoms in schizophrenia. This study is a pilot cross-sectional analysis investigating the relation of plasma CRP levels and the positive and negative symptoms of schizophrenia (the primary aim), assessed by the Positive and Negative Syndrome Scale (PANSS). A secondary analysis was also performed evaluating the potential association of CRP with cognitive function using the NIH Toolbox Cognitive Test Battery. After adjusting for age, sex, race, and body mass index, a positive correlation was observed between CRP and PANSS negative symptoms (rho = 0.37, p = 0.05). There was no correlation between plasma CRP and any of the NIH Toolbox measures of cognitive function in the unadjusted or adjusted analyses. Though limited by a relatively small sample size and the unavailability of longitudinal data, the correlation between CRP and psychopathology in this sample of patients supports a role for inflammation in the pathophysiology of schizophrenia.

Atherosclerotic cardiovascular disease (ASCVD) is highly heritable, particularly when it occurs at a young age. The screening of individuals with premature ASCVD, although often recommended, is not routinely performed. Strategies to address this gap in care are essential. We designed the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) as a prospective, observational study of individuals with a new diagnosis of very premature ASCVD (defined as age ≤ 50 years in males and age ≤ 55 years in females) and their first-degree relatives (FDRs) and spouses. FDRs and spouses will undergo screening for cardiovascular (CV) risk factors and subclinical ASCVD using a structured screening algorithm. All subjects will be followed longitudinally for ≥10 years. The overall goal of SAVE BC is to evaluate the yield of a structured screening program for identifying individuals at risk of premature ASCVD. The primary objectives of SAVE BC are to identify and follow index cases with very premature ASCVD and their FDRs and to determine the diagnostic yield of a structured screening program for these individuals. We will collect data on CV risk factors, medication use, CV events, and healthcare costs in these individuals. SAVE BC will provide insight regarding approaches to identify individuals at risk for premature ASCVD with implications for prevention and treatment in this population.

BACKGROUND: Impairments in selective attention and their neurophysiologic concomitants early in the course of psychotic illness remain relatively understudied. Our recent data provided evidence for disruptions in the attention-related electrophysiological responses among individuals following their first psychotic break (FESz). Specifically, FESz exhibited reduced amplitudes of the N2pc component compared to healthy controls (HC) during a target detection task. The present investigation additionally used the magnetoencephalography (MEG) data that had been simultaneously recorded during selective attention task performance to identify disruptions in source-resolved cortical regions underlying the N2pc impairment. METHODS: MEG and EEG were simultaneously recorded from 22 first-episode schizophrenia spectrum (FESz) and 22 healthy control (HC) individuals during two target detection tasks that required different degrees of top-down attentional control; pop-out and visual search. MEG and EEG sensor locations were coregistered with structural MRI scans for each participant and the boundary element method was used to model the forward solution. The inverse solution for cortical activity contributing to the N2pc signal (275 – 325ms post stimulus) was then derived using the noise covariance matrix calculated from the baseline period of each trial. BA7, BA39, and BA37 were selected a priori as regions of interests (ROIs) based on previous investigations of N2pc sources. Average activity during the N2pc time window was compared between groups using a 2 (task condition) x 2 (group) x 3 (ROI) ANOVA. RESULTS: A significant interaction between group and task condition was observed (F1,42=5.3, p=.03). HC exhibited marginally increased activity during pop-out compared to FESz (t42=1.86, p=.07) despite a statistically equivalent level of activity during visual search (t42=-0.86, p=.39). There were no main effects of group (p=.54), task condition (p=.90), or ROI (p=.94). Nor were there interactions between ROI and group (p=.81) or ROI and task (p=.16). Whereas no correlations between ROI activity and N2pc were observed among FESz (p’s>.05), larger BA37 during visual search activity was associated with larger N2pc scalp amplitudes in HC (r=-.65, p=.001). DISCUSSION: In contrast to the simple group difference in N2pc amplitude recorded from the scalp, examination of the cortical dynamics contributing to this response revealed a differential effect of task condition between groups. FESz exhibited reduced activity relative to HC on target pop-out trials compared to those requiring a top-down, serial search of potential target stimuli. While this finding appears counterintuitive, it may reflect a hyperfocusing of attention on distractor stimuli in our FESz group recently described in a study of individuals with schizophrenia. This mechanism would explain the relative preservation of attention-related cortical activity in FESz during a task with increased distractor interference. The difference between our sensor-level N2pc results based on EEG recordings and our source-level cortical activity derived from simultaneously recorded EEG and MEG speaks to the importance of utilizing complementary imaging modalities to enrich our understanding of processes involved in complex cognitive functions.

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm.The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT).[(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power.This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Multiple studies confirm that African Americans are less likely than non-Hispanic whites to receive needed mental health services. Research has consistently shown that African Americans are under-represented in outpatient mental health treatment settings and are over-represented in inpatient psychiatric settings. Further, African Americans are more likely to receive a diagnosis of schizophrenia and are less likely receive an affective disorder diagnosis during inpatient psychiatric hospitalization compared to non-Hispanic white patients, pointing to a need for examining factors contributing to mental health disparities. Using Andersen's Behavioral Model of Health Service Use, this study examined predisposing, enabling and need factors differentially associated with health service utilization among African American and non-Hispanic white patients (n = 5183) during psychiatric admission. We conducted univariate and multivariate logistic regression analyses to examine both main effects and interactions. In the multivariate model, African American race at admission was predicted by multiple factors including younger age, female gender, multiple psychiatric hospitalizations, elevated positive and negative symptoms of psychosis, a diagnosis of schizophrenia and substance use, as well as having housing and commercial insurance. Additionally, screening positive for cannabis use at intake was found to moderate the relationship between being female and African American. Our study findings highlight the importance of examining mental health disparities using a conceptual framework developed for vulnerable populations (such as racial minorities and patients with co-occurring substance use).

Context processing involves a flexible and continually updated representation of task relevant information and is a core aspect of cognitive control. The expectancy AX Continuous Performance Test (AXCPT) was designed to specifically measure context processing and has been widely applied to elucidate mechanisms of cognitive control and their impairments in conditions such as aging and schizophrenia. Here we present a large-sample, cross-sectional study of context processing aimed at characterizing its normal development from childhood to early adulthood (8 to 22 years old). We track the age-related changes in the standard AXCPT performance measures and also investigate their validity using detailed data-driven method. We show how critical maturational changes in context processing can be validly tracked from mid-adolescence onward with increasing reliance on preparatory, proactive strategies well into early adulthood. However, the early maturation from childhood into adolescence showed a sharp, two-fold discontinuity: while standard measures provide partially conflicting results suggesting an early worsening of proactive strategies, further analyses do not support their validity during this period. Our findings advocate the existence of multiple preparatory strategies that cannot be captured by indices that assume a simple dichotomy of proactive vs. reactive strategies. When evaluating context processing differences over development or in clinical populations, we advocate the explicit testing of the assumptions underlying standard AXCPT indices through complementary data-driven methods.

Repeated viewing of an image over days and weeks induces a marked reduction in the strength with which neurons in monkey inferotemporal cortex respond to it. The processing advantage that attaches to this reduction is unknown. One possibility is that truncation of the response to a familiar image leaves neurons in a state of readiness to respond to ensuing images and thereby enhances their ability to track rapidly changing displays. We explored this possibility by assessing neuronal responses to familiar and novel images in rapid serial visual displays. Inferotemporal neurons responded more strongly to familiar than to novel images in such displays. The effect was stronger among putative inhibitory neurons than among putative excitatory neurons. A comparable effect occurred at the level of the scalp potential in humans. We conclude that long-term familiarization sharpens the response dynamics of neurons in both monkey and human extrastriate visual cortex.