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. Author manuscript; available in PMC: 2024 Feb 1.
Published in final edited form as: Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Oct 30;8(2):181–188. doi: 10.1016/j.bpsc.2021.10.013

Contributions of parasympathetic arousal-related activity to cognitive performance in First Episode Psychosis patients and controls

Anita D Barber 1,2,3, Juan A Gallego 1,2,3, Pamela DeRosse 1,2,3, Michael L Birnbaum 1,2,3, Todd Lencz 1,2,3, Sana A Ali 1,2, Ashley Moyett 1,2, Anil K Malhotra 1,2,3
PMCID: PMC9054940  NIHMSID: NIHMS1752891  PMID: 34728433

Abstract

Background:

Cognitive impairment is integral to the pathophysiology of psychosis. Recent findings implicate autonomic arousal-related activity in both momentary fluctuations and individual differences in cognitive performance. Although altered autonomic arousal is common in First Episode Psychosis (FEP) patients, its contribution to cognitive performance is unknown.

Methods:

24 FEP patients (46% male, age = 24.31 (4.27) years) and 24 healthy controls (42% male, age = 27.06 (3.44) years) performed the Multi-Source Interference Task in-scanner with simultaneous pulse oximetry.

First-level models included the cardiac-BOLD regressor, which reflected parasympathetic arousal-related activity and was created by convolving the inter-beat interval at each heartbeat with the hemodynamic response function, in addition to task (congruent, interference, and error) and nuisance (motion and aCompCor physiology) regressors. Group models examined the effect of group or cognitive performance (reaction times * error rate) on arousal-related and task activity, while controlling for sex, age, and Framewise Displacement.

Results:

Parasympathetic arousal-related activity was robust in both groups, but localized to different regions for FEP patients and healthy control subjects. Within both groups, arousal-related activity was significantly associated with cognitive performance across occipital and temporal cortical regions. Greater arousal-related activity in the bilateral prefrontal cortex (BA 9) was related to better performance in healthy controls, but not FEP patients.

Conclusions:

Autonomic arousal circuits contribute to cognitive performance and the pathophysiology of FEP. Arousal-related functional activity is a novel indicator of cognitive ability and should be incorporated into neurobiological models of cognition in psychosis.

Keywords: first episode psychosis, autonomic arousal, attention, alertness, reaction times, thalamocortical

Introduction

Cognitive impairment is a core component of psychotic disorders (PD) (1, 2). It is present at all stages of the disorder including the prodrome, early, and chronic phases as well as in first degree relatives and in individuals who are at genetic high risk for developing PD (3, 4). Functional outcomes are associated with the degree of cognitive impairment, suggesting that improving cognition is critical for improving quality of life in PD (5, 6). While cognitive impairment is integral to psychosis, it does not tend to co-vary with the severity of psychosis symptoms suggesting that the neurobiology of cognitive impairment in psychosis should be understood in its own right (7, 8).

Cognitive control deficits, such as the failure to appropriately ignore distracting information (interference control), have been identified in individuals with First Episode Psychosis (FEP) and Schizophrenia (9). The Anterior Cingulate Cortex (ACC) and Dorsolateral Prefrontal Cortex (DLPFC) have been commonly identified as loci of dysfunction underlying these deficits (10). Lateral prefrontal and frontoparietal circuits are also commonly associated with working memory deficits in schizophrenia (11, 12) and may underlie poor goal maintenance associated with the disorder (13). While the neurobiology of these cognitive control deficits is well-understood, it is less clear whether the same circuits underlie general attention and/or processing speed deficits, which are highly prevalent in PD.

Intra-subject variability in responding, a behavioral indicator reflecting momentary lapses in attention, is elevated in schizophrenia (14). Poor Default Mode Network (DMN) suppression has been associated with intra-subject variability in psychotic and other psychiatric populations (15–18). While this elevated DMN activity plays a critical role in attention deficits, it is still unclear whether it accounts for processing speed deficits and slowed Reaction Times (RTs) that are ubiquitously found in psychotic populations. ISV is typically normalized by mean RT and therefore, does not capture individual differences in processing speed per se.

Recent studies have found that momentary fluctuations in cortical activity track the autonomic arousal state as well as trial-to-trial changes in cognitive performance (19–21). This widespread cortical activity is propagated from basal forebrain or thalamic nuclei, which receive information about autonomic state from the Ascending Reticular Activating System (ARAS). The ARAS originates in brainstem nuclei that are under the direct influence of the autonomic nervous system (22). Both the sympathetic and parasympathetic branches of the autonomic nervous system influence ascending brainstem structures (23) and robust associations between parasympathetic arousal and cognitive performance were recently found in healthy adults (19). Autonomic dysregulation is commonly reported in PD, including faster Heart Rate (HR), lower HR variability, and reduced vagal activity (24–28). Vagal activity has long been linked to improved mental health and cognition (29). Despite this, no studies have yet examined the role of parasympathetic arousal-related brain activity in cognitive impairment in PD.

The current study measured on-going HR and examined parasympathetic arousal-related activation during performance of the Multi-Source Interference Task (MSIT) to determine whether parasympathetic arousal influences cognitive performance in FEP patients and control participants. A cardiac-BOLD regressor modeled brain activity that tracked the degree of momentary changes in parasympathetic arousal. Given our previous findings that parasympathetic arousal is associated with cognition in healthy participants (19), we expected that parasympathetic arousal-related thalamocortical activity would be reduced in FEP patients and would account for differences in cognitive performance. Further, we expected that group differences in parasympathetic arousal-related activity would be distinct from that of task activity on the MSIT.

Methods and Materials

Participants

Twenty-four FEP patients (46% male, age=24.31(4.27) years) and twenty-four controls (42% male, age=27.06(3.44) years) underwent the scanning protocol. 18 of the 24 control participants overlapped with our previous study (19). Two subjects from the previous study were removed because they were a poor match to the FEP patient sample.

All participants passed the following exclusion criteria: (1) serious neurological or endocrine disorder; (2) any medical condition which requires treatment with a medication with psychotropic effects; (3) significant risk of suicidal or homicidal behavior; (4) cognitive or language limitations, or any other factor that would preclude subjects from providing informed consent; (5) contraindications to MRI (e.g. pacemaker); (6) a diagnosis of substance-induced psychosis or psychosis secondary to a general medical condition. FEP status was determined as those patients presenting with acute psychosis who were in the early phase of illness as defined by less than four weeks of cumulative antipsychotic medication exposure. In order to minimize exposure to antipsychotic medication, patients were scanned as soon as possible after admission to the hospital, ideally before antipsychotic medication was administered. FEP patients were required to endorse current positive symptoms ≥4 (moderate) on one or more of these Brief Psychiatric Rating Scale (BPRS) items: hallucinatory behavior, unusual thought content, conceptual disorganization (30, 31). Control participants were excluded for: (1) any lifetime or current psychotic disorder as determined by clinical interview using the SCID-NP (32); or (2) any serious non-psychiatric disorder that could affect brain functioning. In both groups, participants were excluded who had <60% accuracy on any task condition. All participants provided written consent upon reading a description of the study details. The study protocol was approved by the Institutional Review Board of Northwell Health.

Imaging Scan Procedures

All imaging and task procedures were similar to those described previously (19). Briefly here, all participants were scanned on a Siemens Prisma 3-T scanner at the North Shore University Hospital. This included a T1-weighted scan (TR=2400 msec, TE=2.22 msec, voxel size=0.8 mm3, scan length=6 min,38 sec) and four MB-EPI runs (multiband acceleration factor=8, TR=720 msec, TE=33.00 msec, voxel size=2.2×2.2×2.0 mm, scan length=4 min,2 sec) (33) in which the MSIT was performed. Functional runs were acquired in the AP or PA direction and counterbalanced between subjects. The first 13 volumes of each functional run were discarded.

A pulse oximeter sampled blood oxygen saturation every 4.99 milliseconds through a wireless finger clip attached to the participants’ left index finger. This allowed for detection of heartbeats (HBs) and on-going fluctuations in HR in relation to task performance.

All participants performed two practice pre-scan runs and four experimental scan runs of the MSIT. On each trial, three numbers appeared. Participants responded to the number that was different from the other two, ignoring the position of the numbers. Right-hand index, middle, or ring finger responses were made to a correct answer of 1, 2, or 3, respectively. On congruent trials, the target number appeared with two neutral digits (zeros) and the target digit position was congruent with the correct response; while on interference trials, the target number appeared with two incongruent digits and the target digit position was incongruent with the correct response.

Each trial started with the stimulus for 1750 msec, followed by a fixation for 0–1250 msec. On error trials, a feedback slide stating “Incorrect” or “Too Slow” appeared in red font for 500 msec. Each run consisted of 76 MSIT trials and started and ended with a 10 sec rest period. Three additional 10 sec rest periods were included throughout the run. Participants performed alternating runs of 75%:25% or 25%:75% congruent:interference trials.

Data Analysis

Pulse oximetry HR recordings were processed in Matlab2015b using the peakfinder function. Each Inter-Beat Interval (IBI) was converted to seconds. Any IBI greater than 2 seconds, or more than 4 standard deviations from the mean, was interpolated as the average of surrounding IBIs. For the current study, IBI is used when referring to individual HBs within each subject; however, Beats Per Minute (BPM) is used when referring to the average HR for each participant. Faster HR (greater sympathetic arousal) corresponds to a shorter IBI, but more BPM. In contrast, slower HR (greater parasympathetic arousal) corresponds to a longer IBI but fewer BPM. In addition to computing mean HR during MSIT runs, resting HR was computed as the mean HR across the two resting-state scan runs, which were performed prior to the MSIT and totaled ~14 minutes in length.

Images were motion-corrected, co-registered, segmented, normalized, and spatially-smoothed (8-mm FWHM). First-level General Linear Models (GLMs) included task condition regressors (congruent, interference, and error) for each run. Each task regressor consisted of zero-duration impulse functions at each trial start that were convolved with the canonical hemodynamic response function. For congruent and interference trials, additional RT regressors were created in which the height of the regressor was modulated by the trial RT. Cardiac regressors assessing the impact of HR on brain activity included the heartbeat-evoked regressor, which was formed by placing an impulse function at each heartbeat and the cardiac-BOLD regressor, which was formed by parametrically-modulating the amplitude of each heartbeat by the length of each IBI. These regressors were then convolved with the canonical hemodynamic response function (see (19) for more detail). The cardiac-BOLD regressor, which assessed BOLD activity that tracked fluctuations in HR, was the primary independent variable of interest. Since longer IBI reflected slower HR, a stronger association with the cardiac-BOLD regressor indicated greater parasympathetic arousal-related BOLD activity.

Additionally, a number of nuisance regressors of no interest were included. These consisted of 12 motion parameters and CompCor physiological noise regressors (34, 35). As we found previously (19), the subject GLMs had good parameter estimability for all regressors in each subject indicating that the cardiac-BOLD, task, and nuisance regressors were not collinear.

Within each subject, contrasts were created for the following effects of interest across the four runs: cardiac-BOLD activity, task-evoked activity common to both conditions (congruent+interference), and task-evoked activity distinct for each condition (interference-congruent). The subject-level contrast maps, representing the contrast-weighted beta maps, were then entered into group-level GLMs. These tested for the effect of group (FEP patient versus control) and included covariates for sex, age, and scan motion (Framewise Displacement: FD). Cardiac-BOLD contrasts within each group were thresholded at a stringent voxel- and FWE-corrected, cluster-level of p<0.001, according to Random Field Theory (36–38). Group differences in cardiac-BOLD activity as well as MSIT task-evoked activity were then tested using a more liberal voxel- and FWE-corrected, cluster-level threshold of p<0.05 to detect any atypical activity in FEP patients.

A group-level GLM tested whether cardiac-BOLD activity was related to individual differences in task performance (cognitive efficiency=mean correct trial RT*error rate). We examined cognitive efficiency, a cognitive construct that was proposed to reflect the efficiency with which neural networks process cognitive information (39, 40). Individuals who are faster at cognitive performance also tend to display less task-evoked brain activity and thus, are more “efficient” at task performance (39, 40). Cognitive efficiency, therefore, characterizes individual differences in cognitive performance. One potential mechanism for cognitive efficiency is that more efficient participants have greater parasympathetic arousal-related activity. To examine this, a cognitive efficiency covariate was included for each group in addition to the covariates of no interest (group, sex, age, and FD). Significant brain-behavior relationships were then tested by examining whether cognitive efficiency was related to cardiac-BOLD activity within both groups and whether it was differentially related to cardiac-BOLD activity in the two groups. Significant brain-behavior relationships were thresholded at a voxel- and FEW-corrected, cluster-level of p<0.05.

We previously found that cardiac-BOLD activity occurred within the thalamus, which may be a critical pathway for ascending arousal-related activity (19). To determine whether thalamic cardiac-BOLD activity occurred in the current study, small volume correction was done using a thalamus mask (41) that excluded nearby ventricular activation. Within-group and group difference effects in cardiac-BOLD activity were thresholded at a voxel-level of p<0.001 and an FWE-corrected, cluster-level of p<0.05.

Results

Behavioral

FEP patients had a slightly faster mean MSIT HR than controls (Figure 1) (patient HR: 78.54[11.03], control HR: 74.64[10.91]), but this group difference was only significant when two outlier participants with HR >2 SD from the mean were removed (t(45) = 2.36, p=0.023). There was also a trend-level difference in resting HR (t(45) = 1.61, p=0.11), reflecting slightly elevated resting HR in patients (patient HR: 74.79[11.12], control HR: 69.99[7.92]). This faster resting HR in patients suggests that the group difference reflects higher basal HR in patients and not just increased stress/anxiety due to worse task performance.

Figure 1.

Figure 1.

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Heart Rate (Beats per Minute) in Healthy Control and First Episode Psychosis patients.

When comparing HR during the MSIT to that of rest, task HR was significantly faster both in FEP patients (t(23)=3.65,p=0.001) and in controls (t(23)=5.09, p=3.70×10−5), confirming previous studies that cognitive task performance is a cardiovascular challenge. To further ensure that HR-behavior relationships were not due to anxiety, the relationship between HR and anxiety, as measured by the BPRS, was examined. While there was a mild relationship between anxiety and resting HR in patients (r=−0.22, p>0.05), it was not significant. The anxiety-HR relationship was also non-significant for MSIT HR (r=−0.067) in patients, and for both resting (r=−0.024) and MSIT HR (r=−0.096) in controls.

On the MSIT, cognitive performance tended to be worse in FEP (patient congruent RTs: 652.27[122.99], patient interference RTs: 903.55[125.22], patient congruent accuracy: 0.974[0.040], patient interference accuracy: 0.862 [0.170]) than control participants (control congruent RTs: 596.76[85.44], control interference RTs: 867.34[137.74], control congruent accuracy: 0.972[0.056], control interference accuracy: 0.886[0.123]), although not significantly so (congruent RTs: t(47) = 1.81, p=0.077, interference RTs: t(47) = 0.95, p=0.34, congruent accuracy: t(47) = 0.90, p=0.13, interference accuracy: t(47) = 0.57, p=0.57). After controlling for sex and age covariates, overall RTs were significantly slower in patients than controls (t(42)=2.08, p=0.044), while overall error rate was not significantly different (t(42)=0.97, p=0.34). Cognitive efficiency, which was used to examine inter-individual brain-behavior associations, was also not significantly different for the two groups (t(42)=1.26, p=0.21).

MSIT HR was significantly related to RTs in control participants (r=0.473, p=0.020), but not in FEP patients (r=0.071, p=0.745) (Figure 2). Resting HR was likewise significantly related to RTs in controls (r=0.478, p=0.018), but not in FEP patients (r=0.077, p=0.720), suggesting that the relationship in control participants reflected trait autonomic function and did not reflect increased HR due to stress/anxiety from poor cognitive performance per se. To determine whether there was a speed/accuracy tradeoff in FEP patients, we also examined the relationship with error rate. We found that MSIT HR was not significantly related to error rate in either group (control: r=0.120, p=0.576, FEP Patients: r=0.256, p=0.227), although resting HR was marginally related to error rate in patients (control: r=0.134, p=0.532, FEP Patients: r=0.399, p=0.053). This trend relationship with error rate was in the same direction as RTs (i.e. slower HR was associated with better cognitive performance). Due to the potential speed-accuracy tradeoff in FEP patients, we considered individual differences in cognitive performance as the combination of reaction time and error rate (i.e. RT*error rate) rather than just RTs when examining the relationship between cognitive performance and cardiac-BOLD fMRI activity. While MSIT HR was not directly related to cognitive efficiency in either group (control: r=0.163, p=0.447, FEP Patients: r=0.178, p=0.405), using this behavioral metric for brain-behavior analyses allowed us to directly compare the patient and control findings and reduced the number of comparisons.

Figure 2.

Figure 2.

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Both resting and MSIT Heart Rate is associated with RTs in healthy control participants. Resting Heart Rate is related to error rate in FEP patients.

fMRI Cardiac-BOLD and Task-Evoked Activity

As we found previously, cardiac-BOLD activity, reflecting greater fMRI activity with more parasympathetic arousal, was significant within control participants across several occipital, temporal, parietal, frontal, and anterior insular regions (Figure 3, top panel). This activity was highly significant at a voxel- and FWE-corrected, cluster-level significance of p<0.001. Likewise, cardiac-BOLD activity was found within FEP patients, but was less-localized to cortical regions and was instead confined to the striatum and anterior insula (Figure 3, bottom panel). Within patients, this cardiac-BOLD activity was also highly significant at a voxel- and FWE-corrected, cluster-level significance of p<0.001.

Figure 3.

Figure 3.

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Cardiac-BOLD activity during the Multi Source Interference Task in Healthy Control participants (top panel) and First Episode Psychosis patients (bottom panel). Cardiac-BOLD activity was thresholded at a voxel- and cluster-level of p<0.001.

Group differences in cardiac-BOLD activity and task-evoked activity were identified. Cardiac-BOLD activity was greater in controls than FEP patients across temporal and occipital regions at a voxel- and FWE-corrected, cluster-level significance of p<0.05 (Figure 4, top panel). There were no regions with significantly greater cardiac-BOLD activity in patients than controls. For task-evoked activity, a large region within the Medial Prefrontal Cortex (MPFC) was significantly more active in FEP patients than controls across both congruent and interference trials (congruent+interference contrast). This extended to both the ventral and dorsal MPFC, which composes the anterior portion of the DMN (Figure 4, middle panel). Given that this is a region that is suppressed during task activation, greater activity in patients reflected less task-evoked DMN suppression during task performance. Differential task-related activity for the two groups was also found for interference control activity (interference-congruent contrast). Greater interference-related activity in control than FEP participants peaked in the bilateral DLPFC and the ACC (Figure 4, bottom panel) and was also found within the bilateral Inferior Parietal Cortex and insula.

Figure 4.

Figure 4.

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Group differences in cardiac-BOLD activity (bottom panel), congruent+interference trial activity (middle panel), and interference-congruent trial activity (bottom panel) during the Multi Source Interference Task. All group differences in fMRI activity were thresholded at a voxel- and cluster-level of p<0.05.

To determine whether parasympathetic arousal-related activity was associated with cognitive performance, cognitive efficiency brain-behavior associations were examined. Within both FEP patients and controls, cardiac-BOLD activity was inversely related to cognitive efficiency in a broad area that peaked bilaterally within occipital cortex and extended into lateral temporal and medial parietal regions (Figure. 5). This inverse relationship reflected greater parasympathetic arousal-related activity in individuals with lower cognitive efficiency scores (i.e. better cognitive performance). In a bilateral prefrontal cortex region, this brain-behavior relationship was significantly weaker in patients than controls at a voxel- and FWE-corrected, cluster-wise p<0.05 threshold.

Figure 5.

Figure 5.

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Brain-behavior relationships between cardiac-BOLD activity and cognitive efficiency. Blue indicates those voxels with in which there was a negative relationship between cardiac-BOLD activity and cognitive efficiency (i.e. greater parasympathetic arousal-related activity indicated better cognitive performance). Green indicated those voxels in which the negative brain-behavior relationship was weaker in patients than controls. All brain-behavior relationships were thresholded at a voxel- and cluster-level of p<0.05.

Thalamic Cardiac-BOLD Activity

Using small-volume correction in SPM12, significant cardiac-BOLD activity occurred within the thalamus in each group at a voxel-wise p<0.001 and a FWE-corrected, cluster-wise p<0.05. This activity localized to different thalamic regions within each group. In controls, activity peaked in the ventrolateral pulvinar nucleus, consistent with our previous findings (19). In FEP patients, cardiac-BOLD activity peaked in the ventral lateral nucleus of the thalamus. No group differences in arousal-related thalamic activity achieved significance.

Discussion

We identified relationships between autonomic function and cognitive performance in both FEP patients and controls. In controls, participants with slower HR tended to respond faster on the MSIT. This relationship existed for HR during the MSIT, as well as for resting HR, suggesting that it is not just due to a state of anxiety caused by poor performance, and instead reflects trait differences in autonomic function. FEP patients tended to have faster HR overall and HR was also related to cognitive performance. However, for FEP patients, this relationship was between resting HR and error rate, rather than with RTs.

Consistent with our previous findings that parasympathetic arousal-related activity occurs within the thalamus and across a broad set of cortical regions (19), we found robust parasympathetic arousal-related activity during the MSIT in the current study. Within control participants, this activity occurred primarily in cortical regions; while in FEP patients, this activity was confined to the striatum, thalamus, and insula. In line with our previous study (19), stronger parasympathetic arousal-related activity was associated with better cognitive performance. While this relationship generally occurred within both controls and FEP patients, there was a region of the prefrontal cortex in which this relationship was significantly stronger in controls than patients. These findings suggest that parasympathetic arousal-related activity contributes to group differences in cognitive performance.

Altered autonomic function in FEP

The current study found faster HR in FEP patients. This is consistent with previous findings of elevated HR and lower HR variability in PD (24–26, 28). The findings suggest that FEP patients have higher sympathetic/lower parasympathetic arousal. This altered autonomic function may reflect higher basal stress levels, consistent with previous findings based on cortisol and self-report surveys in psychotic populations (42, 43). Stress is a well-known etiological factor contributing to the emergence of PD (44, 45). The HPA-axis stress response is dysregulated in psychotic patients, as evidenced by higher basal cortisol levels, but a lower cortisol response to acute stress (27). HR and parasympathetic vagal activity are also dysregulated in PD; however, little is known about how autonomic brain circuits contribute to cognitive dysfunction in psychosis. During stress induction tasks, both cortisol levels and HR increase; however, HR effects tend to occur earlier (27, 46–48) suggesting that autonomic responses to stress are quicker and precede that of the HPA-axis (49). For this reason, it has previously been proposed that the immediate cognitive effects of stress are due to autonomic function rather than the HPA-axis. The current findings support the role of autonomic function in cognition.

Altered arousal pathways in FEP

We found parasympathetic arousal-related activity in FEP patients that localized primarily to subcortical and insula regions, rather than to distributed cortical regions as found in control participants. This arousal-related activity was significantly greater in control participants than FEP patients in lateral occipital and temporal cortex regions. Further, activity within the thalamus, which may be a critical ascending arousal pathway (50), localized to different subnuclei in the two groups. For the healthy control group, arousal-related activity peaked in the ventrolateral pulvinar, consistent with our previous findings (19). For the FEP patient group, on the other hand, arousal-related activity peaked in the ventral nucleus of the thalamus, a region that is in circuit with striatal regions and therefore may support ascending arousal-related activity in these regions in FEP patients.

Consistent with our expectations, parasympathetic arousal-related activity supported individual differences in cognitive efficiency in both groups. This relationship occurred across a broad set of cortical regions. Greater parasympathetic arousal-related activity was associated with better cognitive performance (i.e. faster RTs and lower error rates as indicated by the cognitive efficiency measure). Further, arousal-related activity in a lateral prefrontal region was significantly related to cognitive performance in controls, but not FEP patients, suggesting that this low arousal-related activity contributes to cognitive impairment in FEP. Previous studies have proposed that more cognitively-efficient individuals tend to have lower task-evoked activity in cognitive control regions and therefore, they use less neural resources for task performance (39, 40). Given that greater arousal-related activity was associated with greater cognitive efficiency in the current study, it may be that greater recruitment of arousal pathways allows more cognitively-efficient individuals to rely less on task-evoked cognitive control pathways.

As noted in our previous study (19), parasympathetic arousal-related activity was distinct from task-evoked activity. FEP patients had reduced task activity related to interference control peaking in the bilateral DLPFC and ACC, consistent with previous studies (10, 51). Further, FEP patients had reduced suppression of MPFC activity, the anterior node of the DMN, across both task conditions. This activity is consistent with reports of poor DMN suppression in psychotic populations both during task performance and at rest (52). While altered task-evoked activity in FEP patients directly reflects cognitive processes underlying cognitive performance, it is remarkable that parasympathetic arousal-related activity, which is not directly linked to task events, predicts individual differences in cognitive performance in both healthy control and FEP patient groups. This activity may therefore, represent a distinct novel neurobiological pathway, reflecting ascending signals from autonomic brainstem and subcortical nuclei (22, 23), that underlies cognitive impairment in FEP.

Limitations

While the current study identified robust parasympathetic arousal-related activity within both healthy controls and FEP patients, the group differences were of small-to-medium effect size and the sample sizes were modest. All findings were FWE-corrected and localized primarily to grey matter. Group differences in interference control activity localized to expected regions that are common to cognitive control in psychosis populations (10, 53). These characteristics support the accuracy of the finding that FEP patients have low parasympathetic arousal-related activity; however, given the potential for false positive error at the reported statistical threshold (54), replication in independent samples is important to validate this result.

The current sample included FEP patients with active psychosis; however, this included a subset with bipolar disorder and depression. Given previous findings that autonomic function is altered in psychosis patients (55–57), we expected that altered arousal-related activity would specifically relate to psychosis. Future studies should compare arousal-related activity between different psychiatric populations to determine whether this is the case.

Finally, while antipsychotic and other medications were restricted prior to the MRI scan session, over half of the FEP patients were exposed to some antipsychotic medication prior to the scan. This included patients treated prior to hospital admission and those who could not be scanned immediately upon hospital admission and were therefore administered one or more doses of antipsychotic treatment before the scan. Therefore, it cannot be ruled out that altered autonomic function and decreased parasympathetic arousal-related activity in the current sample of FEP patients was a secondary effect of antipsychotic medication rather than a primary etiological factor contributing to psychosis pathology.

Table 1.

Study sample demographics and clinical information.

Healthy Control First Episode Psychosis
n 24 24
% male 46 42
% caucasian 41.67 37.5
% african american 41.67 29.17
% asian 16.67 33.33
age 27.06 (3.44) 24.31 (4.27)
hallucinatory behavior 1 (0) 4.17 (1.76)
unusual thought content 1 (0) 5.25 (0.74)
conceptual disorganization 1 (0) 1.83 (1.05)
duration psychosis (weeks) 23.35 (65.24)
heart rate (BPM) 73.01 (10.72) 76.95 (10.82)
correct trial RTs (msec) 727.56 (95.64) 773.05 (112.71)
% error 7.33 (8.64) 8.31 (9.93)
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*

Heart Rate reflects the average over all heartbeats that were concurrent with correct MSIT trials. Heart Rate in the text reflects the average over all heartbeats during MSIT or resting-state runs.

Acknowledgements

Funding for this study was provided by NIMH R01 MH108654 and R21 MH122886. The data included in the current manuscript were previously presented at the 2020 Annual ACNP meeting: ACNP 59th Annual Meeting: Poster Session I. Neuropsychopharmacology (2020) 45:68–169; https://doi.org/10.1038/s41386–020-00890–7.

Financial Disclosures

Dr. Juan Gallego participated in an Alkermes advisory board. Dr. Michael Birnbaum has received research support from Otsuka Pharmaceutical and is a consultant to and shareholder of NorthShore Therapeutics. Dr. Anil Malhotra is a consultant to Genomind Inc, InformedDNA, and Janssen. All other authors report no biomedical financial interests or potential conflicts of interest.

Footnotes

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