A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
Ultra short-term (UST) heart rate variability (HRV) has been used to establish normative HRV values. This study aims to investigate whether HRV metrics can capture changes in HRV from external stimuli, and whether these metrics remain effective under various recording length. Participants completed varying stimulating activities including viewing images, arithmetic tasks, and memory recall of viewed images. SDNN, RMSSD, pNN50, SD2, SD1/SD2, and DFA were extracted from the data. Comparing arithmetic calculation and the first minute of memory recall, SDNN, pNN50, SD2, and SD1/SD2 had significant HRV differences; this suggests that these metrics can distinguish the inherently different stimuli participants were exposed to. However, comparing first minute of viewing with that of the second, SDNN, pNN50, and SD2, presented some significant HRV differences during two inherently similar stimuli. Comparing the first 60-120 s during viewing, SDNN, pNN50, and SD2 also presented significant differences. Our results suggest that SDNN, pNN50, and SD2 may not be robust in evaluating UST HRVs in replacement of the standard short-term HRV. It may be beneficial to analyze multiple HRV metrics, particularly SD1/SD2, to achieve a more holistic understanding of the underlying physiology.
Heart Rate , Humans , Heart Rate/physiology , Time Factors
BACKGROUND: Inhibitory control develops in early childhood, and atypical development may be a measurable marker of risk for the later development of psychosis. Additionally, inhibitory control may be a target for intervention. METHODS: Behavioral performance on a developmentally appropriate Go/No-Go task including a frustration manipulation completed by children ages 3-5 years (early childhood; n = 107) was examined in relation to psychotic-like experiences (PLEs; 'tween'; ages 9-12), internalizing symptoms, and externalizing symptoms self-reported at long-term follow-up (pre-adolescence; ages 8-11). ERP N200 amplitude for a subset of these children (n = 34) with electrophysiological data during the task was examined as an index of inhibitory control. RESULTS: Children with lower accuracy on No-Go trials compared to Go trials in early childhood (F(1,101) = 3.976, p = 0.049), evidenced higher PLEs at the transition to adolescence 4-9 years later, reflecting a specific deficit in inhibitory control. No association was observed with internalizing or externalizing symptoms. Decreased accuracy during the frustration manipulation predicted higher internalizing, F(2,202) = 5.618, p = 0.004, and externalizing symptoms, F(2,202) = 4.663, p = 0.010. Smaller N200 amplitudes were observed on No-Go trials for those with higher PLEs, F(1,101) = 6.075, p = 0.020; no relationship was observed for internalizing or externalizing symptoms. CONCLUSIONS: Long-term follow-up demonstrates for the first time a specific deficit in inhibitory control behaviorally and electrophysiology, for individuals who later report more PLEs. Decreases in task performance under frustration induction indicated risk for internalizing and externalizing symptoms. These findings suggest that pathophysiological mechanisms for psychosis are relevant and discriminable in early childhood, and further, suggest an identifiable and potentially modifiable target for early intervention.
Psychotic Disorders , Child , Humans , Child, Preschool , Adolescent , Psychotic Disorders/diagnosis , Self Report
A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 206 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
Heart Rate Variability (HRV) can be a useful metric to capture meaningful information about heart function. One of the non-linear indices used to analyze HRV, Detrended Fluctuation Analysis (DFA), finds short and long-term correlations in RR intervals to capture quantitative information about variability. This study focuses on the impact of visual and mental stimulation on HRV as expressed via DFA within healthy adults. Visual stimulation can activate the automatic nervous system to directly impact physiological behavior such as heart rate. In this investigation of HRV, 70 participants (21 males) viewed images on a screen followed by a math and recall task. Each viewing segment lasted 2 min and 18 s. The math and memory recall task segment lasted 4 min total. This process was repeated 9 times during which the participants' electrocardiogram was recorded. 37 participants (12 males) opted in for an additional 24-h Holter recording after the viewing and task segments of the study were complete. Participants were randomly assigned to either a pure (organized image presentation) or mixed (random image presentation) image regime for the viewing portion of the study to investigate the impact of the external environment on HRV. DFA α1 was extracted from the RR intervals. Our findings suggest that DFA α1 can differentiate between the viewing [DFA α1 range from 0.96 (SD = 0.25) to 1.08 (SD = 0.22)] and the task segments [DFA α1 range from 1.17 (SD = 0.21) to 1.26 (SD = 0.25)], p < 0.0006 for all comparisons. However, DFA α1 was not able to distinguish between the two image regimes. During the 24-hour follow up, participants had an average DFA α1 = 1.09 (SD = 0.14). In conclusion, our findings suggest a graded response in DFA during short term stimulation and a responsiveness in participants to adjust physiologically to their external environment expressed through the DFA exponent.
People meeting criteria for a clinical high-risk (CHR) for psychosis syndrome frequently represent a heterogeneous, help-seeking, and dynamic population. Among the numerous symptoms and risk factors for psychosis, exposure to trauma stands out as both highly prevalent and poorly understood. Indeed, while up to 80% of individuals meeting criteria for a CHR syndrome report trauma histories, there is currently limited research dedicated to this specific area. This is particularly problematic as trauma is tied to risk for conversion, leads to a range of clinical issues, and contributes to disability and poor quality of life. Fortunately, recent research in the general population has led to a significant evolution in the way trauma is assessed and understood, and further, some studies have indicated that targeted trauma interventions in formal psychotic disorders are highly effective. However, direct adoption is challenging as the CHR syndrome holds a number of unique concerns (e.g., clinical heterogeneity, developmental trauma), and characteristically, involves a developing pediatric or young adult population that also comes with specific considerations (e.g., living with caregivers, transitionary period in roles). In this "perspective" we frame the issues around understanding trauma in CHR individuals, discuss viable treatments and unique considerations, and provide suggestions for future steps in developing and incorporating trauma-focused interventions in this population.
The goal of this study is to investigate patterns that emerge in brain and heart signals in response to external stimulating image regimes. Data were collected from 84 subjects of ages 18-22. Subjects viewed a series of both neutrally and negatively arousing pictures during 2-min and 18-s-long segments repeated nine times. Both brain [electroencephalogram (EEG)] and heart signals [electrocardiogram (EKG)] were recorded for the duration of the study (ranging from 1.5 to 2.5 h) and analyzed using nonlinear techniques. Specifically, the fractal dimension was computed from the EEG to determine how this voltage trace is related to the image sequencing. Our results showed that subjects visually stimulated by a series of mixed images (a randomized set of neutrally or negatively arousing images) had a significantly higher fractal dimension compared to subjects visually triggered by pure images (an organized set of either all neutral or all negatively arousing images). In addition, our results showed that subjects who performed better on memory recall had a higher fractal dimension computed from the EEG. Analysis of EKG also showed greater heart rate variability in subjects who viewed a series of mixed images compared to subjects visually triggered by pure images. Overall, our results show that the healthy brain and heart are responsive to environmental stimuli that promote adaptability, flexibility, and agility.
Electroencephalography , Fractals , Adolescent , Adult , Electrocardiography , Heart , Heart Rate , Humans , Young Adult
Kraepelinian theory posits that schizophrenia (SZ) is a degenerative disorder that worsens throughout the lifespan. Behavioral studies of cognition have since challenged that viewpoint, particularly in the early phases of illness. Nonetheless, the extent to which cognition remains functionally stable during the early course of illness is unclear, particularly with regard to task-associated connectivity in cognition-related brain networks. In this study, we examined the 1-year stability of the frontoparietal control network during the AX-Continuous Performance Task (AX-CPT) from a new baseline sample of 153 participants scanned at 3T, of which 29 recent onset individuals with SZ and 42 healthy control (HC) participants had follow-up data available for analysis. Among individuals that had both baseline and follow-up data, reduced functional connectivity in SZ was observed between the dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex (SPC) during the high control (B cue) condition. Furthermore, this deficit was stable over time, as no significant time × diagnosis interaction or effects of time were observed and intraclass correlation coefficients were greater than 0.6 in HCs and SZ. Previous 1.5T findings showing stable deficits with no evidence of degeneration in performance or DLPFC activation in an independent SZ sample were replicated. Overall, these results suggest that the neuronal circuitry supporting cognitive control is stably impaired during the early course of illness in SZ across multiple levels of analysis with no evidence of functional decline.
Enhanced emotional memory (EEM) describes memory benefits for emotional items, traditionally attributed to impacts of arousal at encoding; however, attention, semantic relatedness, and distinctiveness likely also contribute in various ways. The current study manipulated arousal, semantic relatedness, and distinctiveness while recording changes in event-related potentials and heart rate during memory encoding. Trials were classified as remembered or forgotten by immediate recall performance. Negative images were remembered significantly better than neutral, and related neutral images were remembered significantly better than unrelated neutral images. Higher P300 and late positive potential (LPP) amplitudes were associated with memory for negative images as compared with related neutral images, suggesting that negative images received additional attentional processing at encoding, and that this cannot be accounted for only by the inherent relatedness of negative stimuli. No encoding benefits were found for related neutral images though they were better remembered than unrelated neutral images, indicating retrieval dynamics impacted memory. When image types were intermixed, greater heart rate changes occurred, and negative and unrelated neutral images received increased elaborative processing as compared with related neutral images, perhaps due to the prioritization of encoding resources. These results suggest encoding and retrieval processes contribute to EEM, with emotional items benefiting additively.
