Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. METHODS: In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. RESULTS: Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. CONCLUSIONS: Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

On predictability of individual functional connectivity networks from clinical characteristics.

In recent years, understanding functional brain connectivity has become increasingly important as a scientific tool with potential clinical implications. Statistical methods, such as graphical models and network analysis, have been adopted to construct functional connectivity networks for single subjects. Here we focus on studying the association between functional connectivity networks and clinical characteristics such as psychiatric symptoms and diagnoses. Utilizing machine learning algorithms, we propose a method to examine predictability of functional connectivity networks from clinical characteristics. Our methods can identify salient clinical characteristics predictive of the whole brain network or specific subnetworks. We illustrate our methods on the analysis of fMRI data in the Philadelphia Neurodevelopmental Cohort study, demonstrating clinically meaningful results.

Network segregation varies with neural distinctiveness in sensorimotor cortex.

Normal aging is associated with declines in sensorimotor function. Previous studies have linked age-related behavioral declines to decreases in neural differentiation (i.e., dedifferentiation), including decreases in the distinctiveness of neural activation patterns and in the segregation of large-scale neural networks at rest. However, no studies to date have explored the relationship between these two neural measures and whether they explain the same aspects of behavior. To investigate these issues, we collected a battery of sensorimotor behavioral measures in older and younger adults and estimated (a) the distinctiveness of neural representations in sensorimotor cortex and (b) sensorimotor network segregation in the same participants. Consistent with prior findings, sensorimotor representations were less distinct and sensorimotor resting state networks were less segregated in older compared to younger adults. We also found that participants with the most distinct sensorimotor representations exhibited the most segregated sensorimotor networks. However, only sensorimotor network segregation was associated with individual differences in sensorimotor performance, particularly in older adults. These novel findings link network segregation to neural distinctiveness, but also suggest that network segregation may play a larger role in maintaining sensorimotor performance with age.

Predicting psychosis risk using a specific measure of cognitive control: a 12-month longitudinal study.

BACKGROUND: Identifying risk factors of individuals in a clinical-high-risk state for psychosis are vital to prevention and early intervention efforts. Among prodromal abnormalities, cognitive functioning has shown intermediate levels of impairment in CHR relative to first-episode psychosis and healthy controls, highlighting a potential role as a risk factor for transition to psychosis and other negative clinical outcomes. The current study used the AX-CPT, a brief 15-min computerized task, to determine whether cognitive control impairments in CHR at baseline could predict clinical status at 12-month follow-up. METHODS: Baseline AX-CPT data were obtained from 117 CHR individuals participating in two studies, the Early Detection, Intervention, and Prevention of Psychosis Program (EDIPPP) and the Understanding Early Psychosis Programs (EP) and used to predict clinical status at 12-month follow-up. At 12 months, 19 individuals converted to a first episode of psychosis (CHR-C), 52 remitted (CHR-R), and 46 had persistent sub-threshold symptoms (CHR-P). Binary logistic regression and multinomial logistic regression were used to test prediction models. RESULTS: Baseline AX-CPT performance (d-prime context) was less impaired in CHR-R compared to CHR-P and CHR-C patient groups. AX-CPT predictive validity was robust (0.723) for discriminating converters v. non-converters, and even greater (0.771) when predicting CHR three subgroups. CONCLUSIONS: These longitudinal outcome data indicate that cognitive control deficits as measured by AX-CPT d-prime context are a strong predictor of clinical outcome in CHR individuals. The AX-CPT is brief, easily implemented and cost-effective measure that may be valuable for large-scale prediction efforts.

Neural distinctiveness declines with age in auditory cortex and is associated with auditory GABA levels.

Neural activation patterns in the ventral visual cortex in response to different categories of visual stimuli (e.g., faces vs. houses) are less selective, or distinctive, in older adults than in younger adults, a phenomenon known as age-related neural dedifferentiation. In this study, we investigated whether neural dedifferentiation extends to the auditory cortex. Inspired by previous animal work, we also investigated whether individual differences in GABA are associated with individual differences in neural distinctiveness in humans. 20 healthy young adults (ages 18-29) and 23 healthy older adults (over 65) completed a functional magnetic resonance imaging (fMRI) scan, during which neural activity was estimated while they listened to music and foreign speech. GABA levels in the auditory, ventrovisual and sensorimotor cortex were estimated in the same individuals in a separate magnetic resonance spectroscopy (MRS) scan. Relative to the younger adults, the older adults exhibited both (1) less distinct activation patterns for music vs. speech stimuli and (2) lower GABA levels in the auditory cortex. Also, individual differences in auditory GABA levels (but not ventrovisual or sensorimotor GABA levels) were associated with individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that age-related neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults.

Sensorimotor network segregation declines with age and is linked to GABA and to sensorimotor performance.

Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.

Michigan Neural Distinctiveness (MiND) study protocol: investigating the scope, causes, and consequences of age-related neural dedifferentiation.

BACKGROUND: Aging is often associated with behavioral impairments, but some people age more gracefully than others. Why? One factor that may play a role is individual differences in the distinctiveness of neural representations. Previous research has found that neural activation patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less distinctive) in older vs. young participants, a phenomenon referred to as age-related neural dedifferentiation. Furthermore, older people whose neural representations are less distinctive tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral consequences of neural dedifferentiation. This protocol paper describes the study rationale and methods being used in complete detail, but not the results (data collection is currently underway). METHODS: The MiND project consists of two studies: the main study and a drug study. In the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR spectroscopy, and diffusion weighted imaging sessions, providing data on neural distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 older adults to compare neural distinctiveness, measured with fMRI, after participants take a placebo or a benzodiazepine (lorazepam) that should increase GABA activity. DISCUSSION: By collecting multimodal imaging measures along with extensive behavioral measures from the same subjects, we are linking individual differences in neurochemistry, neural representation, and behavioral performance, rather than focusing solely on group differences between young and old participants. Our findings have the potential to inform new interventions for age-related declines. TRIAL REGISTRATION: This study was retrospectively registered with the ISRCTN registry on March 4, 2019. The registration number is ISRCTN17266136 .

Eye gaze perception in bipolar disorder: Self-referential bias but intact perceptual sensitivity.

OBJECTIVES: Deficits in social cognition predict poor functional outcome in severe mental illnesses such as schizophrenia and autism. However, research findings on social cognition in bipolar disorder (BD) are sparse and inconsistent. This study aimed to characterize a critical social cognitive process-eye gaze perception-and examine its functional correlates in BD to inform psychopathological mechanisms. METHODS: Thirty participants with BD, 37 healthy controls (HC), and 46 psychiatric controls with schizophrenia (SZ) completed an eye-contact perception task. They viewed faces with varying gaze directions, head orientations, and emotion, and made eye-contact judgments. Psychophysics methods were used to estimate perception thresholds and the slope of the perception curve, which were then compared between the groups and correlated with clinical and functional measures using Bayesian inference. RESULTS: Compared with HC, patients with BD over-perceived eye contact when gaze direction was ambiguous, and this self-referential bias was similar to that in SZ. Patients with BD had lower thresholds (i.e., needed weaker eye-contact signal to start perceiving gaze as self-directed) but a similar slope compared with HC. Regression analyses showed that steeper slope predicted better socio-emotional functioning in HC and SZ, but not in BD. CONCLUSIONS: The psychopathology of social dysfunction was fundamentally different between BD and SZ in this modest sample. Eye gaze perception in BD was characterized by a self-referential bias but preserved perceptual sensitivity, the latter of which distinguished BD from SZ. The relationship between gaze perception and broader socio-emotional functioning in SZ and HC was absent in BD.

Neural circuitry of emotion regulation: Effects of appraisal, attention, and cortisol administration.

Psychosocial well-being requires effective regulation of emotional responding in context of threat or stress. Neuroimaging studies have focused on instructed, volitional regulation (e.g., reappraisal or distancing), largely ignoring implicit regulation that does not involve purposeful effort to alter emotional experience. These implicit processes may or may not involve the same neural pathways as explicit regulatory strategies. We examined the neurobiology of implicit emotional regulation processes and the impact of the stress hormone cortisol on these processes. Our study task employed composite pictures of faces and places to examine neural activity during implicit emotional processing (of emotional faces), while these responses were implicitly regulated by attention shift away from the emotionally evocative stimuli, and while subjects reflectively appraised their own emotional response to them. Subjects completed the task in an fMRI scanner after random assignment to receive placebo or hydrocortisone (HCT), an orally administered version of cortisol. Implicit emotional processing activated insula/IFG, dACC/dMPFC, midbrain and amygdala. With attention shifting, we saw diminished signal in emotion generating/response regions (e.g., amygdala) and increased activations in task specific attention regions like parahippocampus. With appraisal of emotions, we observed robust activations in medial prefrontal areas, where activation is also seen in instructed reappraisal studies. We observed no main effects of HCT administration on brain, but males and females showed opposing neural effects in prefrontal areas. The data suggest that different types of emotion regulation utilize overlapping circuits, but with some strategy specific activation. Further study of the dimorphic sex response to cortisol is needed.

Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear.

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus-unconditioned stimulus (CS-US) contingency at different stages of the experiment. Information about the CS-US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS-US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.

The typical development of posterior medial frontal cortex function and connectivity during task control demands in youth 8-19years old.

To characterize the development of neural substrate for interference processing and task control, this study examined both linear and non-linear effects of age on activation and connectivity during an interference task designed to engage the posterior medial frontal cortex (pMFC). Seventy-two youth, ages 8-19years, performed the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI). With increasing age, overall performance across high-interference incongruent and low-interference congruent trials became faster and more accurate. Effects of age on activation to interference- (incongruent versus congruent conditions), error- (errors versus correct trials during the incongruent condition) and overall task-processing (incongruent plus congruent conditions, relative to implicit baseline) were tested in whole-brain voxel-wise analyses. Age differentially impacted activation to overall task processing in discrete sub-regions of the pMFC: activation in the pre-supplementary motor area (pre-SMA) decreased with age, whereas activation in the dorsal anterior cingulate cortex (dACC) followed a non-linear (i.e., U-shaped) pattern in relation to age. In addition, connectivity of pre-SMA with anterior insula/frontal operculum (AI/FO) increased with age. These findings suggest differential development of pre-SMA and dACC sub-regions within the pMFC. Moreover, as children age, decreases in pre-SMA activation may couple with increases in pre-SMA-AI/FO connectivity to support gains in processing speed in response to demands for task control.

Short theta burst stimulation to left frontal cortex prior to encoding enhances subsequent recognition memory.

Deep semantic encoding of verbal stimuli can aid in later successful retrieval of those stimuli from long-term episodic memory. Evidence from numerous neuropsychological and neuroimaging experiments demonstrate regions in left prefrontal cortex, including left dorsolateral prefrontal cortex (DLPFC), are important for processes related to encoding. Here, we investigated the relationship between left DLPFC activity during encoding and successful subsequent memory with transcranial magnetic stimulation (TMS). In a pair of experiments using a 2-session within-subjects design, we stimulated either left DLPFC or a control region (Vertex) with a single 2-s train of short theta burst stimulation (sTBS) during a semantic encoding task and then gave participants a recognition memory test. We found that subsequent memory was enhanced on the day left DLPFC was stimulated, relative to the day Vertex was stimulated, and that DLPFC stimulation also increased participants' confidence in their decisions during the recognition task. We also explored the time course of how long the effects of sTBS persisted. Our data suggest 2 s of sTBS to left DLPFC is capable of enhancing subsequent memory for items encoded up to 15 s following stimulation. Collectively, these data demonstrate sTBS is capable of enhancing long-term memory and provide evidence that TBS protocols are a potentially powerful tool for modulating cognitive function.

Atypical psychotic symptoms and Dandy-Walker variant.

New-onset psychotic symptoms often respond well to antipsychotic treatment; however, symptoms may be difficult to treat when an underlying brain malformation is present. Here, we present a case of atypical psychotic symptoms in the context of a congenital cerebellar malformation (Dandy-Walker variant). The patient ultimately improved with paliperidone palmitate after multiple antipsychotic medication trials (both oral and one long-acting injectable) were ineffective. Neuroimaging may provide valuable diagnostic and prognostic information in cases of new-onset psychosis with atypical features and treatment resistance, even in the absence of neurologic signs and symptoms.

The Persistence of Experience: Prior Attentional and Emotional State Affects Network Functioning in a Target Detection Task.

Efficient, adaptive behavior relies on the ability to flexibly move between internally focused (IF) and externally focused (EF) attentional states. Despite evidence that IF cognitive processes such as event imagination comprise a significant amount of awake cognition, the consequences of internal absorption on the subsequent recruitment of brain networks during EF tasks are unknown. The present functional magnetic resonance imaging (fMRI) study employed a novel attentional state switching task. Subjects imagined positive and negative events (IF task) or performed a working memory task (EF task) before switching to a target detection (TD) task also requiring attention to external information, allowing for the investigation of neural functioning during external attention based on prior attentional state. There was a robust increase of activity in frontal, parietal, and temporal regions during TD when subjects were previously performing the EF compared with IF task, an effect that was most pronounced following negative IF. Additionally, dorsolateral prefrontal cortex was less negatively coupled with ventromedial prefrontal and posterior cingulate cortices during TD following IF compared with EF. These findings reveal the striking consequences for brain activity following immersion in an IF attentional state, which have strong implications for psychiatric disorders characterized by excessive internal focus.

Error-processing abnormalities in pediatric anxiety and obsessive compulsive disorders.

Anxiety and obsessive compulsive disorders are among the earliest occurring psychopathology and may derive from atypical maturation of neural networks for error processing. Psychological models have alternately suggested that over-detection of errors, excessive caring about errors, or failure of errors to elicit regulatory control could associate with the expression of anxiety. In this review article, the potential relevance of error processing for anxiety and obsessive compulsive disorders is described in the context of neurophysiological and functional magnetic resonance imaging (fMRI) research demonstrating altered brain response to errors in pediatric and adult patients. Finally, hypotheses about developmentally sensitive mechanisms of anxiety and obsessive compulsive disorders are drawn from the extant literature, and avenues for clinical translation are discussed.

Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population.

OBJECTIVE: Since a poor diet is often cited as a contributor to metabolic syndrome for subjects diagnosed with bipolar disorder and schizophrenia, we sought to examine dietary intake, cigarette smoking, and physical activity in these populations and compare them with those for the general population. METHODS: Individuals diagnosed with bipolar disorder (n = 116) and schizophrenia (n = 143) were assessed for dietary intake, lifestyle habits, and metabolic syndrome and compared to age-, gender-, and race-matched subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Additionally, matched subgroups within the patient populations were compared to elicit any differences. RESULTS: As expected, the metabolic syndrome rate was higher in the samples with bipolar disorder (33%) and schizophrenia (47%) compared to matched NHANES controls (17% and 11%, respectively), and not different between the patient groups. Surprisingly, both subjects with bipolar disorder and those with schizophrenia consumed fewer total calories, carbohydrates and fats, as well as more fiber (p < 0.03), compared to NHANES controls. No dietary or activity differences between patient participants with and without metabolic syndrome were found. Subjects with schizophrenia had significantly lower total and low-density cholesterol levels (p < 0.0001) compared to NHANES controls. Subjects with bipolar disorder smoked less (p = 0.001), exercised more (p = 0.004), and had lower body mass indexes (p = 0.009) compared to subjects with schizophrenia. CONCLUSIONS: Counter to predictions, few dietary differences could be discerned between schizophrenia, bipolar disorder, and NHANES control groups. The subjects with bipolar disorder exhibited healthier behaviors than the patients with schizophrenia. Additional research regarding metabolic syndrome mechanisms, focusing on non-dietary contributions, is needed.

Lateral Prefrontal Stimulation of Active Cortex With Theta Burst Transcranial Magnetic Stimulation Affects Subsequent Engagement of the Frontoparietal Network.

BACKGROUND: A critical unanswered question about therapeutic transcranial magnetic stimulation is what patients should do during treatment to optimize its effectiveness. Here, we address this lack of knowledge in healthy participants, testing the hypotheses that stimulating the left dorsolateral prefrontal cortex (dlPFC) while participants perform a working memory task will provide stronger effects on subsequent activation, perfusion, connectivity, and performance than stimulating resting dlPFC. METHODS: After a baseline functional magnetic resonance imaging session to localize dlPFC activation and the associated frontoparietal network (FPN) engaged by an n-back task, healthy participants (N = 40, 67.5% female) underwent 3 counterbalanced sessions, separated by several weeks, during which they received intermittent theta burst stimulation (iTBS) followed by magnetic resonance imaging scans as follows: 1) iTBS to the dlPFC while resting passively (passive), 2) iTBS to the dlPFC while performing the n-back task (active), and 3) iTBS to a vertex site, while not engaged in the n-back task and resting passively (control). RESULTS: We found no difference in n-back performance between the 3 conditions. However, FPN activation was reduced while performing the n-back task in the active condition relative to the passive and control conditions. There was no differential activity in the FPN on comparing passive with control conditions, i.e., there was no effect of the site of stimulation. We found no effects of state or site of stimulation on perfusion or connectivity with the dlPFC. CONCLUSIONS: In this study, the state of the brain while receiving iTBS affected FPN activation, possibly reflecting greater efficiency of FPN network activation when participants were stimulated while engaging the FPN.

Changes in Brain Network Connections After Exposure and Response Prevention Therapy for Obsessive-Compulsive Disorder in Adolescents and Adults.

BACKGROUND: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control. METHODS: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks. RESULTS: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group. CONCLUSIONS: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP.

Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: Changes in resting frontostriatal functional connectivity relevant to positive mood.

Depression is associated with diminished positive affect (PA), postulated to reflect frontostriatal reward circuitry disruptions. Depression has consistently been associated with higher dorsomedial prefrontal cortex (dmPFC) activation, a region that regulates PA through ventral striatum (VS) connections. Low PA in depression may reflect dmPFC's aberrant functional connectivity (FC) with the VS. To test this, we applied theta burst stimulation (TBS) to dmPFC in 29 adults with depression (79% female, Mage = 21.4, SD = 2.04). Using a randomized, counterbalanced design, we administered 3 types of TBS at different sessions: intermittent (iTBS; potentiating), continuous (cTBS; depotentiating), and sham TBS (control). We used neuronavigation to target personalized dmPFC targets based on VS-dmPFC FC. PA and negative affect (NA), and resting-state fMRI were collected pre- and post-TBS. We found no changes in PA or NA with time (pre/post), condition (iTBS, cTBS, sham), or their interaction. Functional connectivity (FC) between the nucleus accumbens and dmPFC showed a significant condition (cTBS, iTBS, and sham) by time (pre-vs. post-TBS) interaction, and post-hoc testing showed decreased pre-to post-TBS for cTBS but not iTBS or sham. For cTBS only, reduced FC pre/post stimulation was associated with increased PA (but not NA). Our findings lend support to the proposed mechanistic model of aberrant FC between the dmPFC and VS in depression and suggest a way forward for treating depression in young adults. Future studies need to evaluate multi-session TBS to test clinical effects.