Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response.

Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD.

Striatal volume and functional connectivity correlate with weight gain in early-phase psychosis.

Second-generation antipsychotic drugs (SGAs) are essential in the treatment of psychotic disorders, but are well-known for inducing substantial weight gain and obesity. Critically, weight gain may reduce life expectancy for up to 20-30 years in patients with psychotic disorders, and prognostic biomarkers are generally lacking. Even though other receptors are also implicated, the dorsal striatum, rich in dopamine D2 receptors, which are antagonized by antipsychotic medications, plays a key role in the human reward system and in appetite regulation, suggesting that altered dopamine activity in the striatal reward circuitry may be responsible for increased food craving and weight gain. Here, we measured striatal volume and striatal resting-state functional connectivity at baseline, and weight gain over the course of 12 weeks of antipsychotic treatment in 81 patients with early-phase psychosis. We also included a sample of 58 healthy controls. Weight measurements were completed at baseline, and then weekly for 4 weeks, and every 2 weeks until week 12. We used linear mixed models to compute individual weight gain trajectories. Striatal volume and whole-brain striatal connectivity were then calculated for each subject, and used to assess the relationship between striatal structure and function and individual weight gain in multiple regression models. Patients had similar baseline weights and body mass indices (BMI) compared with healthy controls. There was no evidence that prior drug exposure or duration of untreated psychosis correlated with baseline BMI. Higher left putamen volume and lower sensory motor connectivity correlated with the magnitude of weight gain in patients, and these effects multiplied when the structure-function interaction was considered in an additional exploratory analysis. In conclusion, these results provide evidence for a correlation of striatal structure and function with antipsychotic-induced weight gain. Lower striatal connectivity was associated with more weight gain, and this relationship was stronger for higher compared with lower left putamen volumes.

Deconstructing Avolition: Initiation vs persistence of reward-directed effort.

Avolition, a decrease in the initiation and persistence of goal-directed behavior, is a critical determinant of disability in patients with schizophrenia. Recent studies have demonstrated that avolition can be modeled using reward-based, behavioral paradigms. These studies suggest that avolition represents a motivational deficit, accounted for by a diminished ability to anticipate pleasurable experiences. Notably, although data suggest that "initiation" and "persistence" of goal-directed behavior may depend on different processes, few studies have sought to distinguish between these two components of avolitional symptoms. Such distinctions could have real consequences for the development and evaluation of interventions designed to ameliorate avolitional symptoms. Thus, the present study examined the relationship between anticipatory pleasure, a key driver of avolition, and both the initiation and persistence of reward-directed, effortful responding during the Effort Expenditures for Rewards Task in 103 healthy participants. We found that anticipatory pleasure was not significantly predictive of the initiation of effortful responding but was significantly predictive of the persistence of effortful responding; most notably when the probabilities of reward and non-reward were equivalent. These data suggest that although deficits in reward processes contribute to the likelihood of persisting in reward-driven behavior, they contribute little to the initiation of such behavior.

Age-Normative Pathways of Striatal Connectivity Related to Clinical Symptoms in the General Population.

BACKGROUND: Altered striatal development contributes to core deficits in motor and inhibitory control, impulsivity, and inattention associated with attention-deficit/hyperactivity disorder and may likewise play a role in deficient reward processing and emotion regulation in psychosis and depression. The maturation of striatal connectivity has not been well characterized, particularly as it relates to clinical symptomatology. METHODS: Resting-state functional connectivity with striatal subdivisions was examined for 926 participants (8-22 years of age, 44% male) from the general population who had participated in two large cross-sectional studies. Developing circuits were identified and growth charting of age-related connections was performed to obtain individual scores reflecting relative neurodevelopmental attainment. Associations of clinical symptom scales (attention-deficit/hyperactivity disorder, psychosis, depression, and general psychopathology) with the resulting striatal connectivity age-deviation scores were then tested using elastic net regression. RESULTS: Linear and nonlinear developmental patterns occurred across 231 striatal age-related connections. Both unique and overlapping striatal age-related connections were associated with the four symptom domains. Attention-deficit/hyperactivity disorder severity was related to age-advanced connectivity across several insula subregions, but to age-delayed connectivity with the nearby inferior frontal gyrus. Psychosis was associated with advanced connectivity with the medial prefrontal cortex and superior temporal gyrus, while aberrant limbic connectivity predicted depression. The dorsal posterior insula, a region involved in pain processing, emerged as a strong contributor to general psychopathology as well as to each individual symptom domain. CONCLUSIONS: Developmental striatal pathophysiology in the general population is consistent with dysfunctional circuitry commonly found in clinical populations. Atypical age-normative connectivity may thereby reflect aberrant neurodevelopmental processes that contribute to clinical risk.

Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study.

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (1H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.

Neural correlates of weight gain with olanzapine.

CONTEXT Iatrogenic obesity caused by atypical antipsychotics increases the rate of death from all causes. Olanzapine is a commonly prescribed atypical antipsychotic medication that frequently causes weight gain. To our knowledge, the neural correlates of this weight gain have not been adequately studied in humans. OBJECTIVE To test the hypothesis that olanzapine treatment disrupts the neural activity associated with the anticipation and receipt (consumption) of food rewards (chocolate milk and tomato juice). DESIGN Event-related functional magnetic resonance imaging study, before and after a 1-week treatment with olanzapine. SETTING A university neuroimaging center. PARTICIPANTS Twenty-five healthy individuals. MAIN OUTCOME MEASURES Changes in blood oxygen level-dependent activations to the anticipation and receipt of food rewards after olanzapine treatment. RESULTS One week of olanzapine treatment caused significant increases in weight, food consumption, and disinhibited eating. Our imaging data showed enhanced activations in the inferior frontal cortex, striatum, and anterior cingulate cortex to the anticipation of a food reward. Activation in the caudate and putamen were enhanced to the receipt of the rewarding food. We also found a decrease in reward responsivity to receipt of the rewarding food in the lateral orbital frontal cortex, an area of the brain thought to exercise inhibitory control on feeding. CONCLUSIONS Olanzapine treatment enhanced both the anticipatory and consummatory reward responses to food rewards in the brain reward circuitry that is known to respond to food rewards in healthy individuals. We also noted a decrease in responsivity to food consumption in a brain area thought to inhibit feeding behavior.

Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression.

BACKGROUND: Major depression (MDD) is characterized by altered emotion processing and deficits in cognitive control. In cognitive interference tasks, patients with MDD have shown excessive amygdala activity and under-recruitment of dorsolateral prefrontal cortex (DLPFC). The purpose of this study was to examine the effects of antidepressant treatment on anomalous neural activity in cognitive-control and emotion-processing circuitry. METHODS: Functional magnetic resonance imaging was conducted on depressed patients (n=23) (both before and after antidepressant treatment) compared with matched controls (n=18) while they performed a cognitive task involving attended and unattended fear-related stimuli. RESULTS: After eight weeks of SSRI antidepressant treatment, patients with depression showed significantly increased DLPFC activity to unattended fear-related stimuli and no longer differed from controls in either DLPFC or amygdala activity. CONCLUSIONS: These results suggest that antidepressant treatment increases DLPFC under-activity during cognitive tasks that include emotional interference. LIMITATIONS: The sample was fairly homogeneous and this may limit generalizability.

Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression.

BACKGROUND: Major depression is characterized by a negativity bias: an enhanced responsiveness to, and memory for, affectively negative stimuli. However, it is not yet clear whether this bias represents 1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or 2) enhanced bottom-up responses to affectively laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function. METHODS: We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 control participants was tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli. RESULTS: Compared with control subjects, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast, control participants showed increased activity in right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not show. In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on posterror trials), but the control group did show them. CONCLUSIONS: These results suggest multiple sources of dysregulation in emotional and cognitive control circuitry in depression, implicating both top-down and bottom-up dysfunction.

Backward inhibition in Parkinson's disease.

Parkinson's disease has been associated with executive dysfunction, especially task-switching deficits. One factor contributing to task-switching costs is backward inhibition, as measured by less efficient performance when switching back to a task from which one has recently switched away. This alternating-switch cost is considered to be due to persisting inhibition of elements of the previous task set after a switch. In this study, patients with mild to moderate Parkinson's disease and controls performed three tasks (A-C) in an intermixed fashion. Patients with mild to moderate Parkinson's disease and controls showed equivalent response times. However, the patients made significantly more errors during an alternating switch (i.e., ABA) than did control participants. In contrast, there was no group difference in accuracy in the comparable condition of two consecutive switches between different tasks (i.e., CBA). In addition, accuracy for the two groups was similar for trials in which the task was repeated. These data suggest that Parkinson's disease is associated with either increased backward inhibition, or a reduced ability to overcome this inhibition when reactivating a recently abandoned task set.

Working memory and relational reasoning in Klinefelter syndrome.

Klinefelter syndrome (KS) is a sex chromosome abnormality associated with male infertility and mild cognitive deficits. Individuals with KS have been reported to have impaired verbal ability, as well as deficits in executive function. To further understand the nature of their deficits, we assessed specific elements of frontal lobe function such as working memory and relational reasoning. Men with KS exhibited a deficit in a transitive inference task in which participants ordered a set of names based on a list of propositions about the relative heights of the people named. This deficit was present even for items in which the propositions were given in order, so a chaining strategy could be used. Men with KS are also impaired on the n-back task, which uses letters as stimuli. In contrast, these men performed as well as controls in nonverbal reasoning (Raven's Progressive Matrices). These results suggest that men with KS have intact nonverbal reasoning abilities, but that a difficulty in encoding verbal information into working memory may underlie their executive and linguistic impairments.

Recruitment of anterior dorsolateral prefrontal cortex in human reasoning: a parametric study of relational complexity.

Reasoning and problem solving depend on the ability to represent and integrate complex relationships among stimuli. For example, deciding whether an animal is dangerous requires integrating information about the type of animal, its size, its distance from oneself, and one's proximity to shelter. Relational complexity increases with the number of such interdependent elements that must be simultaneously considered to solve a problem. We used functional magnetic resonance imaging to identify brain regions that respond selectively in processing high levels of relational complexity. Performance on nonverbal reasoning problems in which relational complexity was varied parametrically was compared with performance on control problems in which relational complexity was held constant while difficulty was manipulated by adding distractor forms to the problems. Increasing complexity and adding distractors both led to increased activation in parietal and in dorsolateral prefrontal cortex, with high levels of relational complexity selectively activating anterior left prefrontal cortex. Our data provide evidence that brain regions specific to integrating complex relations among stimuli are distinct from those involved in coping with general task difficulty and with working-memory demands.