Vijay A. Mittal

Stress and the Hypothalamic Pituitary Adrenal Axis in the Developmental Course of Schizophrenia

Diathesis-stress models of schizophrenia and other psychotic disorders have dominated theorizing about etiology for over three decades. More recently, with advances in our understanding of the biological processes mediating the effects of stress, these models have incorporated mechanisms to account for the adverse impact of stress on brain function. This review examines recent scientific findings on the role of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary neural systems triggered by stress exposure, in the expression of vulnerability for schizophrenia. The results indicate that psychotic disorders are associated with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms. The cumulative findings are discussed in light of a neural diathesis-stress model that postulates that cortisol has the potential to increase activity of dopamine pathways that have been implicated in schizophrenia and other psychotic disorders.

Gene-Environment Interaction and Covariation in Schizophrenia: The Role of Obstetric Complications

While genetic factors account for a significant proportion of liability to schizophrenia, a body of evidence attests to a significant environmental contribution. Understanding the mechanisms through which genetic and environmental factors coalesce in influencing schizophrenia is critical for elucidating the pathways underlying psychotic illness and for developing primary prevention strategies. Although obstetric complications (OCs) remain among the most well-documented environmental indicators of risk for schizophrenia, the pathogenic role they play in the etiology of schizophrenia continues to remain poorly understood. A question of major importance is do these factors result from a genetic diathesis to schizophrenia (as in gene-environment covariation), act additively or interactively with predisposing genes for the disorder in influencing disease risk, or independently cause disease onset? In this review, we evaluate 3 classes of OCs commonly related to schizophrenia including hypoxia-associated OCs, maternal infection during pregnancy, and maternal stress during pregnancy. In addition, we discuss several mechanisms by which OCs impact on genetically susceptible brain regions, increasing constitutional vulnerability to neuromaturational events and stressors later in life (ie, adolescence), which may in turn contribute to triggering psychosis.

Alterations in Brain Structures Related to Taste Reward Circuitry in Ill and Recovered Anorexia Nervosa and in Bulimia Nervosa

OBJECTIVE The pathophysiology of anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. The authors assessed taste pleasantness and reward sensitivity in relation to brain structure, which may be related to food avoidance commonly seen in eating disorders. METHOD The authors used structural MR imaging to study gray and white matter volumes in women with current restricting-type anorexia nervosa (N=19), women recovered from restricting-type anorexia nervosa (N=24), women with bulimia nervosa (N=19), and healthy comparison women (N=24). RESULTS All eating disorder groups exhibited increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manual tracing confirmed larger gyrus rectus volume, and volume predicted taste pleasantness ratings across all groups. Analyses also indicated other morphological differences between diagnostic categories. Antero-ventral insula gray matter volumes were increased on the right side in the anorexia nervosa and recovered anorexia nervosa groups and on the left side in the bulimia nervosa group relative to the healthy comparison group. Dorsal striatum volumes were reduced in the recovered anorexia nervosa and bulimia nervosa groups and predicted sensitivity to reward in all three eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas relative to the healthy comparison group. The results held when a range of covariates, such as age, depression, anxiety, and medications, were controlled for. CONCLUSION Brain structure in the medial orbitofrontal cortex, insula, and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value.

The relations among putative biorisk markers in schizotypal adolescents: minor physical anomalies, movement abnormalities, and salivary cortisol.

BACKGROUND Evidence suggests that prenatal insult may play a role in the etiology of psychotic disorders. Minor physical anomalies (MPA) are an indicator of abnormal fetal development and are elevated in individuals at genetic and behavioral risk for psychosis. Yet, there has been little empirical research on the relationships between MPAs and other neurobiological risk indicators. We hypothesized that the frequency of MPAs (an external marker of prenatal central nervous system [CNS] disruption) would be associated with two other biomarkers suggestive of disruptions in fetal neurodevelopment: movement abnormalities (an indicator of striatal abnormalities) and heightened cortisol secretion (an indicator of hypothalamic-pituitary-adrenal [HPA]/hippocampal function). METHODS Participants with schizotypal personality disorder (SPD; n = 39) and both normal (n = 47) and other personality disorders (n = 28) control subjects were administered structured diagnostic interviews and assessed for MPAs, movement abnormalities, and salivary cortisol. RESULTS Schizotypal personality disorder participants showed significantly greater MPAs and movement abnormalities and higher cortisol than both the normal and other personality disorders groups. Hierarchical linear regression analyses revealed that higher rates of MPAs were linked with greater movement abnormalities and salivary cortisol. CONCLUSIONS The findings suggest that MPAs serve as a marker of neurodevelopmental abnormalities that affect striatal and hippocampal regions.

Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia.

CONTEXT Because recent findings suggest that early treatment may ameliorate the course or even prevent the onset of schizophrenia and other psychotic disorders, longitudinal high-risk research on biological markers of risk has become a priority. Within this context, premorbid movement abnormalities are of particular interest because the neurocircuitry hypothesized to give rise to dyskinetic movements has also been implicated in psychotic symptoms. To date, there have been no published longitudinal studies examining the progression of movement abnormalities and their relation with symptom progression in at-risk youth. OBJECTIVE To examine the progression of movement abnormalities in relation to positive and negative symptoms in adolescents at high risk of developing psychotic disorders. DESIGN Naturalistic, prospective, longitudinal design. SETTING Participants recruited through announcements directed at parents of adolescents showing schizotypal symptoms. PARTICIPANTS One hundred twenty-one adolescents (mean baseline age, 14.26 years), 32 with schizotypal personality disorder, 49 nonclinical controls, and 40 with other personality disorders. MAIN OUTCOME MEASURES Participating adolescents were evaluated for personality disorders (Structured Interview for DSM-IV Personality Disorders), prodromal symptoms (Structured Interview for Prodromal Symptoms), and movement abnormalities (Dyskinesia Identification System Condensed User Scale) at 3 annual assessments. RESULTS The schizotypal group exhibited significantly elevated movement abnormalities in comparison with controls across all 3 time points. Further, the schizotypal personality disorder group alone showed significant increases in movement abnormalities over time. Movement abnormalities were correlated with prodromal symptoms at each time period, and for several body regions, the magnitude of this relationship significantly increased over time. CONCLUSIONS The results are consistent with the hypothesis of shared neural circuitry for movement abnormalities and psychotic symptoms and suggest the potential value of including an assessment of motor signs in screening for psychosis risk.

Longitudinal Study of Stressful Life Events and Daily Stressors Among Adolescents at High Risk for Psychotic Disorders

Psychosocial stress preceding the onset or recurrence of psychotic symptoms has been identified in patients with schizophrenia; yet there is limited understanding of the effects of stress in typically developing adolescents or those who show behavioral signs of risk for schizophrenia spectrum disorders. This study examined the developmental course of symptom progression as a function of stressful life events and daily hassles in adolescents with schizotypal personality disorder (SPD), other personality disorders, or no Axis II disorder. In this prospective longitudinal study, life events and daily stressors were assessed in adolescents aged 12 to 18 years. Results revealed that adolescents with SPD and other personality disorders reported significantly greater total, independent, and undesirable life events than individuals with no Axis II disorders. Youth with SPD report daily hassles to cause more distress compared to peers. Correlational analyses and hierarchal linear regression was used to evaluate the relationship of life events and daily stressors with psychiatric symptoms measured concurrently and 1 year later. Across diagnostic groups, the incidence of independent and undesirable life events were associated with current prodromal symptoms, while the frequency of daily stressors predicted a significant increment in positive, but not negative, prodromal symptoms over time. Therefore, adolescents who report greater daily stressors exhibit an increase in prodromal symptoms over a 1 year period. Psychosocial stress has been implicated in the etiology of schizophrenia, and these findings suggest the importance of life events and daily hassles as potential risk factors in the onset of psychotic symptoms during adolescence.

Movement abnormalities predict conversion to Axis I psychosis among prodromal adolescents.

Evidence suggests that movement abnormalities are a precursor of psychosis. The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The authors coded movement abnormalities from videotapes of 40 adolescents at risk for psychosis (designated prodromal on the Structured Interview for Prodromal Symptoms; T. J. Miller et al., 2002). Following initial assessment, participants were evaluated for diagnostic status at 4 times annually. Ten participants converted to an Axis I psychosis (e.g., schizophrenia) over the 4-year period. Comparisons of converted and nonconverted participants at baseline indicated that the groups did not differ on demographic characteristics or levels of prodromal symptomatology, but those who converted exhibited significantly more movement abnormalities. Movement abnormalities and prodromal symptoms were strongly associated and logistic regression analyses indicated that abnormalities in the face and upper body regions were most predictive of conversion. Findings suggest that individuals with elevated movement abnormalities may represent a subgroup of prodromal adolescents who are at the highest risk for conversion. The implications for neural mechanisms and for identifying candidates for preventive intervention are discussed.

Markers of Basal Ganglia Dysfunction and Conversion to Psychosis: Neurocognitive Deficits and Dyskinesias in the Prodromal Period

BACKGROUND Movement abnormalities and cognitive deficits may represent external markers of an underlying neural process linked with the early etiology of psychosis. As basal ganglia function plays a governing role in both movement and cognitive processes, an understanding of the relationship between these phenomena stands to inform etiologic conceptualizations of vulnerability and psychotic disorders. METHODS In this investigation, trained raters coded movement abnormalities in videotapes from structured interviews of adolescents and young adults with a prodromal risk syndrome (n = 90). The participants were administered a neuropsychological battery including measures of verbal comprehension, perceptual organization, immediate/delayed auditory memory, and an estimate of full-scale intelligence quotient. Diagnostic status was followed for a 2-year period utilizing structured clinical interviews, during which time 24 high-risk participants (26.66%) converted to an Axis I psychotic disorder. RESULTS Elevated dyskinetic movements in the upper-body region were correlated with deficits in domains of verbal comprehension, perceptual organization, and both immediate and delayed auditory memory. Further, discriminant function analyses indicated that baseline movement abnormalities and neurocognitive deficits significantly classified those high-risk participants who would eventually convert to a psychotic disorder (72.3%). CONCLUSIONS Results support a common cortico-striato-pallido-thalamic circuit irregularity, underlying both movement abnormalities and cognitive deficits in individuals at high risk for psychosis. Models incorporating external markers of progressive basal ganglia dysfunction may enhance detection and preventive intervention for those high-risk individuals most in need of treatment.

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.