Joseph M. Orr

Orbitofrontal Cortex Volume and Brain Reward Response in Obesity

Background/objectives:What drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function.Subjects/methods:We examined obese (n=18, age=28.7±8.3 years) and healthy control women (n=24, age=27.4±6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function.Results:Obese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals.Conclusions:This study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity.

Cerebellar networks in individuals at ultra high-risk of psychosis: impact on postural sway and symptom severity.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high‐risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum‐a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello‐cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello‐cortical resting state connectivity, relative to controls. The decreased cerebello‐cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum‐based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations. Hum Brain Mapp 35:4064–4078, 2014.

Sleep dysfunction and thalamic abnormalities in adolescents at ultra high-risk for psychosis.

BACKGROUND Sleep dysfunction is a pervasive, distressing characteristic of psychosis, yet little is known regarding sleep quality prior to illness onset. At present, it is unclear whether sleep dysfunction precedes the emergence of psychotic symptoms, signifying a core feature of the disorder, or if it represents a consequence of prolonged contact with aspects of schizophrenia and its treatment (e.g., medication use or neurotoxicity) or co-morbid symptoms (e.g., depressive and manic symptomatology). The current study examined sleep dysfunction in adolescents at ultra high-risk (UHR) for psychosis, relationships between sleep disturbances and psychosis symptoms, volume of an integral sleep-structure (thalamus), and associations between thalamic abnormalities and sleep impairment in UHR youth. METHOD Thirty-three UHR youth and 33 healthy controls (HC) participated in a self-assessment of sleep functioning (Pittsburgh Sleep Quality Index; PSQI), self and parent-report clinical interviews, and structural magnetic resonance imaging (MRI). RESULTS UHR adolescents displayed increased latency to sleep onset and greater sleep disturbances/disrupted continuity compared to HC youth, over and above concurrent mood symptoms. Among UHR youth, increased sleep dysfunction was associated with greater negative symptom severity but not positive symptoms. Compared to HC adolescents, UHR participants displayed decreased bilateral thalamus volume, which was associated with increased sleep dysfunction. CONCLUSIONS Sleep dysfunction occurs during the pre-psychotic period, and may play a role in the etiology and pathophysiology of psychosis. In addition, the relationship of disrupted sleep to psychosis symptoms in UHR youth indicates that prevention and intervention strategies may be improved by targeting sleep stabilization in the pre-psychotic period.

The Organization of Right Prefrontal Networks Reveals Common Mechanisms of Inhibitory Regulation Across Cognitive, Emotional, and Motor Processes

Inhibitory control/regulation is critical to adapt behavior in accordance with changing environmental circumstances. Dysfunctional inhibitory regulation is ubiquitous in neurological and psychiatric populations. These populations exhibit dysfunction across psychological domains, including memory/thought, emotion/affect, and motor response. Although investigation examining inhibitory regulation within a single domain has begun outlining the basic neural mechanisms supporting regulation, it is unknown how the neural mechanisms of these domains interact. To investigate the organization of inhibitory neural networks within and across domains, we used neuroimaging to outline the functional and anatomical pathways that comprise inhibitory neural networks regulating cognitive, emotional, and motor processes. Networks were defined at the group level using an array of analyses to indicate their intrinsic pathway structure, which was subsequently assessed to determine how the pathways explained individual differences in behavior. Results reveal how neural networks underlying inhibitory regulation are organized both within and across domains, and indicate overlapping/common neural elements.

Widespread brain dysconnectivity associated with psychotic-like experiences in the general population

It is becoming increasingly clear that psychosis occurs along a continuum. At the high end are formal psychotic disorders such as schizophrenia, and at the low-end are individuals who experience occasional psychotic symptoms, but are otherwise healthy (non-clinical psychosis, NCP). Schizophrenia has been shown to be marked by altered patterns of connectivity between brain regions, but it is not known if such dysconnectivity exists in NCP. In the current study we used functional magnetic resonance imaging (fMRI) to compare resting-state functional connectivity in NCP individuals (n = 25) and healthy controls (n = 27) for four brain networks of interest (fronto-parietal, cingulo-opercular, default mode, and cerebellar networks). NCP individuals showed reduced connectivity compared to controls between regions of the default mode network and frontal regions, and between regions in all of the networks and the thalamus. NCP individuals showed greater connectivity compared to controls within regions of frontal control networks. Further, positive symptom scores in NCP individuals were positively correlated with connectivity between the cingulo-opercular network and the visual cortex, and were negatively correlated with connectivity between the cerebellar network and the posterior parietal cortex and dorsal premotor cortex. Connectivity was not correlated with positive symptom scores in controls. Taken together, these findings demonstrate that a spectrum of abnormal connectivity underlies the psychosis continuum, and that individuals with sub-clinical psychotic experiences represent a key population for understanding pathogenic processes.

Organization of the Human Frontal Pole Revealed by Large-Scale DTI-Based Connectivity: Implications for Control of Behavior

The goal of the current study was to examine the pattern of anatomical connectivity of the human frontal pole so as to inform theories of function of the frontal pole, perhaps one of the least understood region of the human brain. Rather than simply parcellating the frontal pole into subregions, we focused on examining the brain regions to which the frontal pole is anatomically and functionally connected. While the current findings provided support for previous work suggesting the frontal pole is connected to higher-order sensory association cortex, we found novel evidence suggesting that the frontal pole in humans is connected to posterior visual cortex. Furthermore, we propose a functional framework that incorporates these anatomical connections with existing cognitive theories of the functional organization of the frontal pole. In addition to a previously discussed medial-lateral distinction, we propose a dorsal-ventral gradient based on the information the frontal pole uses to guide behavior. We propose that dorsal regions are connected to other prefrontal regions that process goals and action plans, medial regions are connected to other brain regions that monitor action outcomes and motivate behaviors, and ventral regions connect to regions that process information about stimuli, values, and emotion. By incorporating information across these different levels of information, the frontal pole can effectively guide goal-directed behavior.

The Neural Mechanisms Underlying Internally and Externally Guided Task Selection

While some prior work suggests that medial prefrontal cortex (MFC) regions mediate freely chosen actions, other work suggests that the lateral frontal pole (LFP) is responsible for control of abstract, internal goals. The present study uses fMRI to determine whether the voluntary selection of a task in pursuit of an overall goal relies on MFC regions or the LFP. To do so, we used a modified voluntary task switching (VTS) paradigm, in which participants choose an individual task to perform on each trial (i.e., a subgoal), under instructions to perform the tasks equally often and in a random order (i.e. the overall goal). In conjunction, we examined patterns of activation in the face of irrelevant, but task-related external stimuli that might nonetheless influence task selection. While there was some evidence that the MFC was involved in voluntary task selection, we found that the LFP and anterior insula (AI) were crucial to task selection in the pursuit of an overall goal. In addition, activation of the LFP and AI increased in the face of environmental stimuli that might serve as an interfering or conflicting external bias on voluntary task choice. These findings suggest that the LFP supports task selection according to abstract, internal goals, and leaves open the possibility that MFC may guide action selection in situations lacking in such top-down biases. As such, the current study represents a critical step towards understanding the neural underpinnings of how tasks are selected voluntarily to enable an overarching goal.

Physical Activity Level and Medial Temporal Health in Youth at Ultra High-Risk for Psychosis

A growing body of evidence suggests that moderate to vigorous activity levels can affect quality of life, cognition, and brain structure in patients diagnosed with schizophrenia. However, physical activity has not been systematically studied during the period immediately preceding the onset of psychosis. Given reports of exercise-based neurogenesis in schizophrenia, understanding naturalistic physical activity levels in the prodrome may provide valuable information for early intervention efforts. The present study examined 29 ultra high-risk (UHR) and 27 matched controls to determine relationships between physical activity level, brain structure (hippocampus and parahippocampal gyrus), and symptoms. Participants were assessed with actigraphy for a 5-day period, MRI, and structured clinical interviews. UHR participants showed a greater percentage of time in sedentary behavior while healthy controls spent more time engaged in light to vigorous activity. There was a strong trend to suggest the UHR group showed less total physical activity. The UHR group exhibited smaller medial temporal volumes when compared with healthy controls. Total level of physical activity in the UHR group was moderately correlated with parahippocampal gyri bilaterally (right: r = .44, left: r = .55) and with occupational functioning (r = -.36; of negative symptom domain), but not positive symptomatology. Results suggest that inactivity is associated with medial temporal lobe health. Future studies are needed to determine if symptoms are driving inactivity, which in turn may be affecting the health of the parahippocampal structure and progression of illness. Although causality cannot be determined from the present design, these findings hold important implications for etiological conceptions and suggest promise for an experimental trial.

Increased postural sway predicts negative symptom progression in youth at ultrahigh risk for psychosis

Impaired ability to maintain an upright posture may reflect impairment in the cerebellum, a critical structure for the fluid coordination of neural information, thought to be disrupted in psychosis. The current study utilized an instrumental measure of posture in individuals at ultrahigh risk (UHR) for psychosis (n=43) and healthy controls (n=44). Positive and negative symptoms were assessed twice over 12months. Results showed that increased postural sway in the UHR group predicted changes in negative symptoms. This study provides an important prospective view on the relationship between cerebellar-sensitive behavior and integral symptoms, which until now has received limited biomarker research.

Cerebellar Morphology and Procedural Learning Impairment in Neuroleptic-Naive Youth at Ultrahigh Risk of Psychosis

Despite evidence suggesting a role for cerebellar abnormalities in the pathogenesis of psychosis, the structure has yet to receive attention in individuals at ultrahigh risk for psychosis (UHR). Accumulating research has suggested that the cerebellum helps modulate cognition and movement, domains in which UHR individuals show impairment; understanding putative markers of risk, such as structural abnormalities and behavioral correlates, is essential. In this study, participants underwent a high-resolution structural brain scan and participated in a pursuit rotor experiment. Cerebellar regions associated with movement (anterior cerebellum) and cognition (crus I) were subsequently analyzed. UHR participants showed impaired performance on the pursuit rotor task, learned at a slower rate, and showed smaller cerebellar volumes compared with control participants. Left crus I volume was significantly associated with poor rate of learning. The present results suggest that cerebellar abnormalities and their behavioral correlates (poor learning and motor control) precede the onset of psychosis.