Bayesian Optimization of Neurostimulation (BOONStim).

BACKGROUND: Transcranial magnetic stimulation (TMS) treatment response is influenced by individual variability in brain structure and function. Sophisticated, user-friendly approaches, incorporating both established functional magnetic resonance imaging (fMRI) and TMS simulation tools, to identify TMS targets are needed. OBJECTIVE: The current study presents the development and validation of the Bayesian Optimization of Neuro-Stimulation (BOONStim) pipeline. METHODS: BOONStim uses Bayesian optimization for individualized TMS targeting, automating interoperability between surface-based fMRI analytic tools and TMS electric field modeling. Bayesian optimization performance was evaluated in a sample dataset (N=10) using standard circular and functional connectivity-defined targets, and compared to grid optimization. RESULTS: Bayesian optimization converged to similar levels of total electric field stimulation across targets in under 30 iterations, converging within a 5% error of the maxima detected by grid optimization, and requiring less time. CONCLUSIONS: BOONStim is a scalable and configurable user-friendly pipeline for individualized TMS targeting with quick turnaround.

Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow.

Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975).

Five negative symptom domains are differentially associated with resting state amplitude of low frequency fluctuations in Schizophrenia.

This study examined associations between resting-state amplitude of low frequency fluctuations (ALFF) and negative symptoms represented by total scores, second-order dimension (motivation and pleasure, expressivity), and first-order domain (anhedonia, avolition, asociality, alogia, blunted affect) factor scores in schizophrenia (n = 57). Total negative symptom scores showed positive associations with ALFF in temporal and frontal brain regions. Negative symptom domain scores showed predominantly stronger associations with regional ALFF compared to total scores, suggesting domain scores may better map to neural signatures than total scores. Improving our understanding of the neuropathology underlying negative symptoms may aid in addressing this unmet therapeutic need in schizophrenia.

Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity.

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10-3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10-6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10-6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10-27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

Tryptophan Challenge in Healthy Controls and People with Schizophrenia: Acute Effects on Plasma Levels of Kynurenine, Kynurenic Acid and 5-Hydroxyindoleacetic Acid.

The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP is metabolized to serotonin and further to 5-hydroxyindoleacetic acid (5-HIAA). Notably, KP metabolism is readily affected by immune stimulation. Here, we assessed the acute effects of an oral TRP challenge (6 g) on peripheral concentrations of kynurenine, KYNA and 5-HIAA, as well as the cytokines interferon-γ, TNF-α and interleukin-6, in 22 participants with SZ and 16 healthy controls (HCs) using a double-blind, placebo-controlled, crossover design. TRP raised the levels of kynurenine, KYNA and 5-HIAA in a time-dependent manner, causing >20-fold, >130-fold and 1.5-fold increases in kynurenine, KYNA and 5-HIAA concentrations, respectively, after 240 min. According to multivariate analyses, neither baseline levels nor the stimulating effects of TRP differed between participants with SZ and HC. Basal cytokine levels did not vary between groups, and remained unaffected by TRP. Although unlikely to be useful diagnostically, measurements of circulating metabolites following an acute TRP challenge may be informative for assessing the in vivo efficacy of drugs that modulate the neosynthesis of KYNA and other products of TRP degradation.

Hallucinations: A Functional Network Model of How Sensory Representations Become Selected for Conscious Awareness in Schizophrenia.

Hallucinations are conscious perception-like experiences that are a common symptom of schizophrenia spectrum disorders (SSD). Current neuroscience evidence suggests several brain areas are involved in the generation of hallucinations including the sensory cortex, insula, putamen, and hippocampus. But how does activity in these regions give rise to aberrant conscious perceptions that seemingly invade ongoing conscious experience? Most existing models assume that sensory representations are sometimes spontaneously activated in the brain, and that these spontaneous activations somehow play a causal role in the generation of hallucinations. Yet, it remains unclear how these representations become selected for conscious processing. No existing theory of hallucinations has specified such a "selection mechanism." Global Workspace (GW) theorists argue that the brain's interconnected processors select relevant piece(s) of information for broadcasting to other brain processors, rendering the information accessible to consciousness; this process known as "ignition" is associated with synchronized activity across distributed cortical and subcortical brain regions. Yet, it remains unclear how certain information and representations become selected for conscious processing. While GW theorists maintain that attention plays an important role, they have not delineated a formal "selection mechanism." This paper specifies a selection mechanism based upon two central hypotheses: (1) a functional network called the "salience network" plays a critical role in selecting sensory representations for conscious broadcast to the GW in normal (healthy) perception; (2) sensory representations become abnormally selected for conscious broadcast to the GW (instead of being filtered out of consciousness) in individuals with SSD that experience hallucinations.

Mapping local and long-distance resting connectivity markers of TMS-related inhibition reduction in schizophrenia.

Short interval intracortical inhibition (SICI) is a biomarker for altered motor inhibition in schizophrenia, but the manner in which distant sites influence the inhibitory cortical-effector response remains elusive. Our study investigated local and long-distance resting state functional connectivity (rsFC) markers of SICI in a sample of N = 23 patients with schizophrenia and N = 29 controls. Local functional connectivity was quantified using regional homogeneity (ReHo) analysis and long-range connectivity was estimated using seed-based rsFC analysis. Direct and indirect effects of connectivity measures on SICI were modeled using mediation analysis. Higher SICI ratios (indicating reduced inhibition) in patients were associated with lower ReHo in the right insula. Follow-up rsFC analyses showed that higher SICI scores (indicating reduced inhibition) were associated with reduced connectivity between right insula and hubs of the corticospinal pathway: sensorimotor cortex and basal ganglia. Mediation analysis supported a model in which the direct effect of local insular connectivity strength on SICI is mediated by the interhemispheric connectivity between insula and left sensorimotor cortex. The broader clinical implications of these findings are discussed with emphasis on how these preliminary findings might inform novel interventions designed to restore or improve SICI in schizophrenia and deepen our understanding of motor inhibitory control and impact of abnormal signaling in motor-inhibitory pathways in schizophrenia.

Multiple dimensions of stress vs. genetic effects on depression.

Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R2 = 0.06, p = 2 × 10-5) and current stress measured by Perceived Stress Scale (R2 = 0.13, p < 1 × 10-6) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R2 = 0.41, p < 1 × 10-6). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h2) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h2 for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.

Local versus long-range connectivity patterns of auditory disturbance in schizophrenia.

Auditory hallucinations are a debilitating symptom of schizophrenia. Effective treatment is limited because the underlying neural mechanisms remain unknown. Our study investigates how local and long-range functional connectivity is associated with auditory perceptual disturbances (APD) in schizophrenia. APD was assessed using the Auditory Perceptual Trait and State Scale. Resting state fMRI data were collected for N=99 patients with schizophrenia. Local functional connectivity was estimated using regional homogeneity (ReHo) analysis; long-range connectivity was estimated using resting state functional connectivity (rsFC) analysis. Mediation analyses tested whether local (ReHo) connectivity significantly mediated associations between long-distance rsFC and APD. Severity of APD was significantly associated with reduced ReHo in left and right putamen, left temporoparietal junction (TPJ), and right hippocampus-pallidum. Higher APD was also associated with reduced rsFC between the right putamen and the contralateral putamen and auditory cortex. Local and long-distance connectivity measures together explained 40.3% of variance in APD (P < 0.001), with the strongest predictor being the left TPJ ReHo (P < 0.001). Additionally, TPJ ReHo significantly mediated the relationship between right putamen - left putamen rsFC and APD (Sobel test, P = 0.001). Our findings suggest that both local and long-range functional connectivity deficits contribute to APD, emphasizing the role of striatum and auditory cortex. Considering the translational impact of these circuit-based findings within the context of prior clinical trials to treat auditory hallucinations, we propose a model in which correction of both local and long-distance functional connectivity deficits may be necessary to treat auditory hallucinations.

The Role of Hippocampal Functional Connectivity on Multisystem Subclinical Abnormalities in Schizophrenia.

OBJECTIVE: Schizophrenia is associated with excess medical mortality: patients have an average life expectancy one to two decades shorter than the general population. This study investigates the relationship between aberrant hippocampal resting-state functional connectivity in schizophrenia and cumulative subclinical effects of chronic stress on metabolic, cardiovascular, and immune function using the allostatic load index. METHODS: Cumulative stress was estimated using allostatic load total score (range, 0-13) in 46 patients with schizophrenia and 31 controls matched for age and sex (patients: age = 36.1 [13.7] years, sex = 32/14 male/female; controls: age = 35.5 [14.1], sex = 21/10 male/female). Hippocampal functional connectivity was assessed using resting-state functional magnetic resonance imaging; hippocampal structural connectivity was assessed using fornix fractional anisotropy. Linear regression analysis was used a) to test the hypothesis that aberrant hippocampal resting-state functional connectivity in schizophrenia (identified in analysis of schizophrenia - control differences) is associated with elevated allostatic load scores in patients and b) to determine the association between fornix fractional anisotropy with allostatic load. RESULTS: In patients, higher allostatic load was significantly associated with reduced resting functional connectivity between the left hippocampus and right cingulate cortex and left precentral gyrus, but higher connectivity between the right hippocampus and left cerebellum lobe VI (corrected p values <. 05). In controls, reductions in both hippocampal structural connectivity and hippocampal-cingulate functional connectivity were associated with higher allostatic load scores. CONCLUSIONS: These findings support basic neuroscience evidence that cumulative stress and hippocampal function are closely connected and suggest that abnormal hippocampal functional communication in schizophrenia may be related to elevated multisystem subclinical medical issues in patients as indexed by allostatic load.

A working memory related mechanism of auditory hallucinations.

Cognitive mechanisms underlying auditory hallucinations (AH) in schizophrenia have been related to working memory (WM), although the formative mechanism is unknown. The phonological loop refers to subvocal rehearsals of information held online for supporting WM. As WM deficiency is frequent in schizophrenia, we hypothesized that AH and WM deficit share a common dysfunction in phonological loop operation, especially when it is taxed by ambiguous auditory and verbal associations. We developed an active phonological priming (APP) paradigm in which participants generated arbitrary verbal associations to pseudowords with ambiguous meaning. They were later asked to rate their familiarity to each pseudoword, a task that required subvocal evaluation of ambiguous auditory-verbal information. Factor and mediation analyses were used to test the hypothesis that WM, AH, and APP induced phonological bias toward perceiving ambiguous contents as familiar may share a common underlying mechanism. In 32 patients with schizophrenia (SZ) and 20 healthy controls (HC), SZ rated ambiguous pseudowords as significantly more familiar compared with HC (p = .006), indicating a proneness to APP-induced bias. This increased subjective bias to perceive ambiguous contents as familiar after APP significantly correlated with AH severity (p = .001) and mediated the relationship between WM and AH. Factor analysis demonstrated a common latent factor among WM, AH, and the bias induced by active priming to ambiguous contents. A heightened phonological loop priming to ambiguous contents appears to be mechanistically linked to WM deficits and AH in schizophrenia. These findings emphasize the importance of jointly addressing WM deficits and AH in clinical practice and research. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Aberrant Frontostriatal Connectivity in Negative Symptoms of Schizophrenia.

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC-striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms.

Salience-Default Mode Functional Network Connectivity Linked to Positive and Negative Symptoms of Schizophrenia.

Schizophrenia is a complex, debilitating mental disorder characterized by wide-ranging symptoms including delusions, hallucinations (so-called positive symptoms), and impaired motor and speech/language production (so-called negative symptoms). Salience-monitoring theorists propose that abnormal functional communication between the salience network (SN) and default mode network (DMN) begets positive and negative symptoms of schizophrenia, yet prior studies have predominately reported links between disrupted SN/DMN functional communication and positive symptoms. It remains unclear whether disrupted SN/DMN functional communication explains (1) solely positive symptoms or (2) both positive and negative symptoms of schizophrenia. To address this question, we incorporate time-lag-shifted functional network connectivity (FNC) analyses that explored coherence of the resting-state functional magnetic resonance imaging signal of 3 networks (anterior DMN, posterior DMN, and SN) with fixed time lags introduced between network time series (1 TR = 2 s; 2 TR = 4 s). Multivariate linear regression analysis revealed that severity of disordered thought and attentional deficits were negatively associated with 2 TR-shifted FNC between anterior DMN and posterior DMN. Meanwhile, severity of flat affect and bizarre behavior were positively associated with 1 TR-shifted FNC between anterior DMN and SN. These results provide support favoring the hypothesis that lagged SN/DMN functional communication is associated with both positive and negative symptoms of schizophrenia.

Disrupted network cross talk, hippocampal dysfunction and hallucinations in schizophrenia.

Hallucinations characterize schizophrenia, with approximately 59% of patients reporting auditory hallucinations and 27% reporting visual hallucinations. Prior neuroimaging studies suggest that hallucinations are linked to disrupted communication across distributed (sensory, salience-monitoring and subcortical) networks. Yet, our understanding of the neurophysiological mechanisms that underlie auditory and visual hallucinations in schizophrenia remains limited. This study integrates two resting-state functional magnetic resonance imaging (fMRI) analysis methods - amplitudes of low-frequency fluctuations (ALFF) and functional network connectivity (FNC) - to explore the hypotheses that (1) abnormal FNC between salience and sensory (visual/auditory) networks underlies hallucinations in schizophrenia, and (2) disrupted hippocampal oscillations (as measured by hippocampal ALFF) beget changes in FNC linked to hallucinations. Our first hypothesis was supported by the finding that schizophrenia patients reporting hallucinations have higher FNC between the salience network and an associative auditory network relative to healthy controls. Hippocampal ALFF was negatively associated with FNC between primary auditory cortex and the salience network in healthy subjects, but was positively associated with FNC between these networks in patients reporting hallucinations. These findings provide indirect support favoring our second hypothesis. We suggest future studies integrate fMRI with electroencephalogram (EEG) and/or magnetoencephalogram (MEG) methods to directly probe the temporal relation between altered hippocampal oscillations and changes in cross-network functional communication.

Modality-Dependent Impact of Hallucinations on Low-Frequency Fluctuations in Schizophrenia.

Prior resting-state functional magnetic resonance imaging (fMRI) analyses have identified patterns of functional connectivity associated with hallucinations in schizophrenia (Sz). In this study, we performed an analysis of the mean amplitude of low-frequency fluctuations (ALFF) to compare resting state spontaneous low-frequency fluctuations in patients with Sz who report experiencing hallucinations impacting different sensory modalities. By exploring dynamics across 2 low-frequency passbands (slow-4 and slow-5), we assessed the impact of hallucination modality and frequency range on spatial ALFF variation. Drawing from a sample of Sz and healthy controls studied as part of the Functional Imaging Biomedical Informatics Research Network (FBIRN), we replicated prior findings showing that patients with Sz have decreased ALFF in the posterior brain in comparison to controls. Remarkably, we found that patients that endorsed visual hallucinations did not show this pattern of reduced ALFF in the back of the brain. These patients also had elevated ALFF in the left hippocampus in comparison to patients that endorsed auditory (but not visual) hallucinations. Moreover, left hippocampal ALFF across all the cases was related to reported hallucination severity in both the auditory and visual domains, and not overall positive symptoms. This supports the hypothesis that dynamic changes in the ALFF in the hippocampus underlie severity of hallucinations that impact different sensory modalities.