Adina S. Fischer

Confirmatory Factor Analysis of the Behavior Rating Inventory of Executive Function-Adult Version in Healthy Adults and Application to Attention-Deficit/Hyperactivity Disorder

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a questionnaire measure designed to assess executive functioning in everyday life. Analysis of data from the BRIEF-A standardization sample yielded a two-factor solution (labeled Behavioral Regulation and Metacognition). The present investigation employed confirmatory factor analysis (CFA) to evaluate four alternative models of the factor structure of the BRIEF-A self-report form in a sample of 524 healthy young adults. Results indicated that a three-factor model best fits the data: a Metacognition factor, a Behavioral Regulation factor consisting of the Inhibit and Self-Monitor scales, and an Emotional Regulation factor composed of the Emotional Control and Shift scales. The three factors contributed 14%, 19%, and 24% of unique variance to the model, respectively, and a second-order general factor accounted for 41% of variance overall. This three-factor solution is consistent with recent CFAs of the Parent report form of the BRIEF. Furthermore, although the Behavioral Regulation factor score in the two-factor model did not differ between adults with attention-deficit/hyperactivity disorder and a matched healthy comparison group, greater impairment on the Behavioral Regulation factor but not the Emotional Regulation factor was found using the three-factor model. Together, these findings support the multidimensional nature of executive function and the clinical relevance of a three-factor model of the BRIEF-A.

Predicting inpatient complications from cerebral aneurysm clipping: the Nationwide Inpatient Sample 2005–2009

OBJECT Precise delineation of individualized risks of morbidity and mortality is crucial in decision making in cerebrovascular neurosurgery. The authors attempted to create a predictive model of complications in patients undergoing cerebral aneurysm clipping (CAC). METHODS The authors performed a retrospective cohort study of patients who had undergone CAC in the period from 2005 to 2009 and were registered in the Nationwide Inpatient Sample (NIS) database. A model for outcome prediction based on preoperative individual patient characteristics was developed. RESULTS Of the 7651 patients in the NIS who underwent CAC, 3682 (48.1%) had presented with unruptured aneurysms and 3969 (51.9%) with subarachnoid hemorrhage. The respective inpatient postoperative risks for death, unfavorable discharge, stroke, treated hydrocephalus, cardiac complications, deep vein thrombosis, pulmonary embolism, and acute renal failure were 0.7%, 15.3%, 5.3%, 1.5%, 1.3%, 0.6%, 2.0%, and 0.1% for those with unruptured aneurysms and 11.5%, 52.8%, 5.5%, 39.2%, 1.7%, 2.8%, 2.7%, and 0.8% for those with ruptured aneurysms. Multivariate analysis identified risk factors independently associated with the above outcomes. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated using the area under the receiver operating characteristic curve, and it was found to have good discrimination. CONCLUSIONS The featured model can provide individualized estimates of the risks of postoperative complications based on preoperative conditions and can potentially be used as an adjunct in decision making in cerebrovascular neurosurgery.

Impaired functional connectivity of brain reward circuitry in patients with schizophrenia and cannabis use disorder: Effects of cannabis and THC.

Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15 mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD.

The Clinical Applicability of Functional Connectivity in Depression: Pathways Toward More Targeted Intervention

Resting-state functional magnetic resonance imaging provides a noninvasive method to rapidly map large-scale brain networks affected in depression and other psychiatric disorders. Dysfunctional connectivity in large-scale brain networks has been consistently implicated in major depressive disorder (MDD). Although advances have been made in identifying neural circuitry implicated in MDD, this information has yet to be translated into improved diagnostic or treatment interventions. In the first section of this review, we discuss dysfunctional connectivity in affective salience, cognitive control, and default mode networks observed in MDD in association with characteristic symptoms of the disorder. In the second section, we address neurostimulation focusing on transcranial magnetic stimulation and evidence that this approach may directly modulate circuit abnormalities. Finally, we discuss possible avenues of future research to develop more precise diagnoses and targeted interventions within the heterogeneous diagnostic category of MDD as well as the methodological limitations to clinical implementation. We conclude by proposing, with cautious optimism, the future incorporation of neuroimaging into clinical practice as a tool to aid in more targeted diagnosis and treatment guided by circuit-level connectivity dysfunction in patients with depression.

Understanding marijuana's effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation

Nearly half of patients with schizophrenia (SCZ) have co-occurring cannabis use disorder (CUD), which has been associated with decreased treatment efficacy, increased risk of psychotic relapse, and poor global functioning. While reports on the effects of cannabis on cognitive performance in patients with SCZ have been mixed, study of brain networks related to executive function may clarify the relationship between cannabis use and cognition in these dual-diagnosis patients. In the present pilot study, patients with SCZ and CUD (n=12) and healthy controls (n=12) completed two functional magnetic resonance imaging (fMRI) resting scans. Prior to the second scan, patients smoked a 3.6% tetrahydrocannabinol (THC) cannabis cigarette or ingested a 15mg delta-9-tetrahydrocannabinol (THC) pill. We used resting-state functional connectivity to examine the default mode network (DMN) during both scans, as connectivity/activity within this network is negatively correlated with connectivity of the network involved in executive control and shows reduced activity during task performance in normal individuals. At baseline, relative to controls, patients exhibited DMN hyperconnectivity that correlated with positive symptom severity, and reduced anticorrelation between the DMN and the executive control network (ECN). Cannabinoid administration reduced DMN hyperconnectivity and increased DMN-ECN anticorrelation. Moreover, the magnitude of anticorrelation in the controls, and in the patients after cannabinoid administration, positively correlated with WM performance. The finding that DMN brain connectivity is plastic may have implications for future pharmacotherapeutic development, as treatment efficacy could be assessed through the ability of therapies to normalize underlying circuit-level dysfunction.

Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder

Importance Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development. Objective To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder. Design, Setting, and Participants A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control). Main Outcomes and Measures We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events. Results Of the 65 participants (mean [SD] age, 18.9 [2.5] years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score = 0.23; P < .001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score = 0.24; P < .001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18 = 0.48; P = .03). Resilient adolescent females had greater connectivity within frontal (z score = 0.07; P < .001) and limbic (z score = 0.21; P < .001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score = 0.13; P < .001) and control (z score = 0.10; P < .001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score = 0.24; P < .001) adolescent females. Conclusions and Relevance Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.

Response to “Cortico-accumbens circuitry in schizophrenia: Merely a reward system?” by Rolland and Jardri (SCHRES-14-D-00731)

Weappreciate the interest of Rolland and Jardri in our paper (Fischer et al., 2014). The authors suggest that the circuitry we observed to be abnormal in patients with schizophrenia and cannabis use disorder, that we and others have noted to be involved in reward processing (Blum et al., 2000; Green, 2007; Di Martino et al., 2008) has also been implicated in “other functional (e.g., salience processing) and dysfunctional (e.g., psychosis)” processes. We agree, and as we noted in our paper, that the use of resting state functional connectivity “does not directly measure response to reward, and the brain regions implicated in the brain reward circuit are also involved in processes other than reward.” Potentially, future research correlating resting state functional connectivity of the implicated circuitry with analyses of task-based data would be helpful, although others have noted correspondence between resting state networks and task-based findings (Di Martino et al., 2008; Fox and Greicius, 2010;Whitfield-Gabrieli and Ford, 2011). In their recent publication, Rolland and colleagues (Rolland et al., 2014) linkedhallucinations in patientswith schizophrenia to connectivity between the nucleus accumbens (NAc), ventral tegmental area (VTA), and a number of other regions generally consistent with what we referred to as the brain reward circuit. Moreover, they noted in their letter that the circuitry that we found to be affected by THC and smoked cannabis has also been implicated in psychosis in schizophrenia, and that smoking cannabis can increase positive symptoms in these patients. As indicated in our paper, however, we noted no global increase in positive or negative symptom severity on the PANSS after cannabis or THC. We recently conducted further analyses on our data, and we found no significant changes in any of the individual positive symptoms of the PANSS, or significant associations between individual positive symptoms and connectivity of reward circuitry, at the dose of THC and the amount of cannabis administered. In our paper, we did propose that the effects of cannabis on reward circuitry may be dosedependent, and thus it is possible that higher doses of cannabis and THC might have worsened positive symptoms. However, while there are important methodological differences between our study and that of Rolland et al (2014), in our study the modest amount of cannabis smoked (1/2 of a 3.6% THC cigarette) and the relatively low dose of THC administered (15 mg THC pill) improved the functional connectivity between regions of the brain reward circuit, primarily observed between the bilateral NAc and regions of the prefrontal (i.e., ventral anterior cingulate) cortex, without worsening psychosis.