NIMH perspectives on future directions in neuroimaging for mental health.

NIMH's mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. New imaging techniques hold great promise for improving our understanding of the pathophysiology of mental illnesses, stratifying patients for treatment selection, and developing a personalized medicine approach. Here, we highlight emerging and promising new technologies that are likely to be vital in helping NIMH accomplish its mission, the potential for utilizing multimodal approaches to study mental illness, and considerations for data analytics and data sharing.

Key Findings from Mental Health Research During the Menopause Transition for Racially and Ethnically Minoritized Women Living in the United States: A Scoping Review.

Background: Racially and ethnically minoritized (REM) women experience social and structural factors that may affect their response to mental health treatment and menopausal symptoms during the menopause transition (MT). This scoping review on mental health during the MT for REM women in the United States was conducted to characterize factors associated with mental health challenges. Materials and Methods: Five databases were searched. Articles were included if focused on MT in REM women in the United States and its territories with specific mental illnesses and published in English from 2005 to 2021. Titles and abstracts and full text were screened. Screening and data collection were completed in duplicate by two reviewers in Covidence. Results: Sixty-five articles were included and indicate that REM women experience a disproportionate burden of depressive symptoms during the MT. Less evidence is reported about anxiety, Post-Traumatic Stress Disorder, psychosis, schizophrenia, and other mental illnesses. The risk factors associated with mental illness during MT are social, structural, and biological. Treatment response to therapeutic interventions is often underpowered to explain REM differences. Conclusion: Depression during the MT is associated with negative outcomes that may impact REM women differentially. Incorporating theoretical frameworks (e.g., intersectionality, weathering) into mental health research will reduce the likelihood that scientists mislabel race as the cause of these inequities, when racism and intersecting systems of oppression are the root causes of differential expression of mental illness among REM women during the MT. There is a need for interdisciplinary research to advance the mental health of REM women.

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).

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.

Linking Salience Signaling With Early Adversity and Affective Distress in Individuals at Clinical High Risk for Psychosis: Results From an Event-Related fMRI Study.

Evidence suggests dysregulation of the salience network in individuals with psychosis, but few studies have examined the intersection of stress exposure and affective distress with prediction error (PE) signals among youth at clinical high-risk (CHR). Here, 26 individuals at CHR and 19 healthy volunteers (HVs) completed a monetary incentive delay task in conjunction with fMRI. We compared these groups on the amplitudes of neural responses to surprising outcomes-PEs without respect to their valence-across the whole brain and in two regions of interest, the anterior insula and amygdala. We then examined relations of these signals to the severity of depression, anxiety, and trauma histories in the CHR group. Relative to HV, youth at CHR presented with aberrant PE-evoked activation of the temporoparietal junction and weaker deactivation of the precentral gyrus, posterior insula, and associative striatum. No between-group differences were observed in the amygdala or anterior insula. Among youth at CHR, greater trauma histories were correlated with stronger PE-evoked amygdala activation. No associations were found between affective symptoms and the neural responses to PE. Our results suggest that unvalenced PE signals may provide unique information about the neurobiology of CHR syndromes and that early adversity exposure may contribute to neurobiological heterogeneity in this group. Longitudinal studies of young people with a range of risk syndromes are needed to further disentangle the contributions of distinct aspects of salience signaling to the development of psychopathology.

Schizophrenia: a disorder of broken brain bioenergetics.

A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.

Relating Glutamate, Conditioned, and Clinical Hallucinations via 1H-MR Spectroscopy.

BACKGROUND AND HYPOTHESIS: Hallucinations may be driven by an excessive influence of prior expectations on current experience. Initial work has supported that contention and implicated the anterior insula in the weighting of prior beliefs. STUDY DESIGN: Here we induce hallucinated tones by associating tones with the presentation of a visual cue. We find that people with schizophrenia who hear voices are more prone to the effect and using computational modeling we show they overweight their prior beliefs. In the same participants, we also measured glutamate levels in anterior insula, anterior cingulate, dorsolateral prefrontal, and auditory cortices, using magnetic resonance spectroscopy. STUDY RESULTS: We found a negative relationship between prior-overweighting and glutamate levels in the insula that was not present for any of the other voxels or parameters. CONCLUSIONS: Through computational psychiatry, we bridge a pathophysiological theory of psychosis (glutamate hypofunction) with a cognitive model of hallucinations (prior-overweighting) with implications for the development of new treatments for hallucinations.

Two Factors, Five Factors, or Both? External Validation Studies of Negative Symptom Dimensions in Schizophrenia.

OBJECTIVES: Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. METHODS: Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). RESULTS: SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. CONCLUSIONS: Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints.

White matter alterations and the conversion to psychosis: A combined diffusion tensor imaging and glutamate 1H MRS study.

INTRODUCTION: Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis. METHODS: Participants included 33 antipsychotic naïve CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis. RESULTS: CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found. CONCLUSION: The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth.

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αß = .22, 95% CI = 0.02, 0.48) and social functioning (αß = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL.

Metabolite Alterations in Adults With Schizophrenia, First Degree Relatives, and Healthy Controls: A Multi-Region 7T MRS Study.

Proton magnetic resonance spectroscopy (MRS) studies in schizophrenia have shown altered GABAergic, glutamatergic, and bioenergetic pathways, but if these abnormalities are brain region or illness-stage specific is largely unknown. MRS at 7T MR enables reliable quantification of multiple metabolites, including GABA, glutamate (Glu) and glutamine (Gln), from multiple brain regions within the time constraints of a clinical examination. In this study, GABA, Glu, Gln, the ratio Gln/Glu, and lactate (Lac) were quantified using 7T MRS in five brain regions in adults with schizophrenia (N = 40), first-degree relatives (N = 11), and healthy controls (N = 38). Metabolites were analyzed for differences between groups, as well as between subjects with schizophrenia with either short (<5 years, N = 19 or long (>5 years, N = 21) illness duration. For analyses between the three groups, there were significant glutamatergic and GABAergic differences observed in the anterior cingulate, centrum semiovale, and dorsolateral prefrontal cortex. There were also significant relationships between anterior cingulate cortex, centrum semiovale, and dorsolateral prefrontal cortex and cognitive measures. There were also significant glutamatergic, GABAergic, and lactate differences between subjects with long and short illness duration in the anterior cingulate, centrum semiovale, dorsolateral prefrontal cortex, and hippocampus. Finally, negative symptom severity ratings were significantly correlated with both anterior cingulate and centrum semiovale metabolite levels. In summary, 7T MRS shows multi-region differences in GABAergic and glutamatergic metabolites between subjects with schizophrenia, first-degree relatives and healthy controls, suggesting relatively diffuse involvement that evolves with illness duration. Unmedicated first-degree relatives share some of the same metabolic characteristics as patients with a diagnosis of schizophrenia, suggesting that these differences may reflect a genetic vulnerability and are not solely due to the effects of antipsychotic interventions.

Multimodal Neuroimaging Study of Visual Plasticity in Schizophrenia.

Schizophrenia is a severe mental illness with visual learning and memory deficits, and reduced long term potentiation (LTP) may underlie these impairments. Recent human fMRI and EEG studies have assessed visual plasticity that was induced with high frequency visual stimulation, which is thought to mimic an LTP-like phenomenon. This study investigated the differences in visual plasticity in participants with schizophrenia and healthy controls. An fMRI visual plasticity paradigm was implemented, and proton magnetic resonance spectroscopy data were acquired to determine whether baseline resting levels of glutamatergic and GABA metabolites were related to visual plasticity response. Adults with schizophrenia did not demonstrate visual plasticity after family-wise error correction; whereas, the healthy control group did. There was a significant regional difference in visual plasticity in the left visual cortical area V2 when assessing group differences, and baseline GABA levels were associated with this specific ROI in the SZ group only. Overall, this study suggests that visual plasticity is altered in schizophrenia and related to basal GABA levels.

Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T.

BACKGROUND: Magnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD). METHODS: Nine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T 1H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling. RESULTS: Baseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms. LIMITATIONS: Sample size. CONCLUSIONS: These preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.

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.

Hippocampus and cognitive domain deficits in treatment-resistant schizophrenia: A comparison with matched treatment-responsive patients and healthy controls✰,✰✰,☠,☠☠.

Some patients with schizophrenia do not respond to pharmacotherapy. More severe cognitive dysfunctions have been associated with treatment-resistant schizophrenia (TRS). This study examines cognitive functions and hippocampal volumes in 43 patients with TRS and compared them to 43 treatment-responsive patients (NTRS), matched on age, sex and education, as well as 53 healthy controls (HC). The results showed that there were significant deficits in all domains of cognition and hippocampal volumes in TRS as compared to HC group. However, TRS specific deficits, as indicated by comparisons with matched NTRS, were limited to poorer performance in working memory (p = 0.003) and smaller total hippocampal volume (p = 0.01). Logistic regression analysis showed that working memory deficits [OR 0.94 (95% CI 0.89-0.98), p = 0.005] and smaller hippocampal volume [OR 0.89 (95% CI 0.81-0.97), p = 0.01], but not their interactions (p = 0.68), contributed to higher risk of treatment resistance. The findings suggest that treatment-resistance to currently available antipsychotic medications may not be due to global cognitive deficits in these patients, but be associated with specific deficits in working memory and hippocampus deficits in the subgroup of schizophrenia.

Evidence of reward system dysfunction in youth at clinical high-risk for psychosis from two event-related fMRI paradigms.

Abnormal reward processing is thought to play an important role in the development of psychosis, but relatively few studies have examined reward prediction errors, reinforcement learning (RL), and the reward circuitry that subserves these interconnected processes among individuals at clinical high-risk (CHR) for the disorder. Here, we present behavioral and functional neuroimaging results of two experimental tasks designed to measure overlapping aspects of reward processing among individuals at CHR (n = 22) and healthy controls (n = 19). We found no group differences in response times to positive, negative, or neutral outcome-signaling cues, and no significant differences in brain activation during reward anticipation or receipt. Youth at CHR, however, displayed clear RL impairments, as well as attenuated responses to rewards and blunted prediction error signals in the ventral striatum, dorsal anterior cingulate cortex (dACC), and ventromedial prefrontal cortex (vmPFC). Greater contrasts for cue valence (gain-loss) and outcome magnitude (large-small) in the vmPFC were associated with more severe negative symptoms, and deficits in dACC signaling during RL were associated with more depressive symptoms. Our results provide evidence for RL deficits and abnormal prediction error signaling in the brain's reward circuitry among individuals at CHR, while also suggesting that reward motivation may be relatively preserved at this stage in development. Longitudinal studies, medication-free participants, and comparison of neurobehavioral measures against both healthy and clinical controls are needed to better understand the role of reward system abnormalities in the development of psychosis.

Cingulum and abnormal psychological stress response in schizophrenia.

Stress is implicated in many aspects of schizophrenia, including heightened distress intolerance. We examined how affect and microstructure of major brain tracts involved in regulating affect may contribute to distress intolerance in schizophrenia. Patients with schizophrenia spectrum disorders (n = 78) and community controls (n = 95) completed diffusion weighted imaging and performed psychological stress tasks. Subjective affect was collected pre and post stressors. Individuals who did not persist during one or both stress tasks were considered distress intolerant (DI), and otherwise distress tolerant (DT). Fractional anisotropy (FA) of the dorsal cingulum showed a significant diagnosis x DT/DI phenotype interaction (p = 0.003). Post-hoc tests showed dorsal cingulum FA was significantly lower in DI patients compared with DI controls (p < 0.001), but not different between DT groups (p = 0.27). Regarding affect responses to stress, irritability showed the largest stress-related change (p < 0.001), but irritability changes were significantly reduced in DI patients compared to DI controls (p = 0.006). The relationship between irritability change and performance errors also differed among patients (ρ = -0.29, p = 0.011) and controls (ρ = 0.21, p = 0.042). Further modeling highlighted the explanatory power of dorsal cingulum for predicting DI even after performance and irritability were taken into account. Distress intolerance during psychological stress exposure is related to microstructural properties of the dorsal cingulum, a key structure for cognitive control and emotion regulation. In schizophrenia, the affective response to psychological stressors is abnormal, and distress intolerant patients had significantly reduced dorsal cingulum FA compared to distress intolerant controls. The findings provide new insight regarding distress intolerance in schizophrenia.