Terri M. Teshiba

Enhanced Cue Reactivity and Fronto-striatal Functional Connectivity in Cocaine Use Disorders

Chronic cocaine use is associated with enhanced cue reactivity to drug stimuli. However, it may also alter functional connectivity (fcMRI) in regions involved in processing drug stimuli. Our aims were to evaluate the neural regions involved in subjective craving and how fcMRI may be altered in chronic cocaine users. Fourteen patients with a confirmed diagnosis of cocaine abuse or dependence (CCA) and 16 gender, age, and education-matched healthy controls (HC) completed a cue reactivity task and a resting state scan while undergoing functional magnetic resonance imaging. CCA showed increased activation compared to HC in left dorsolateral prefrontal and bilateral occipital cortex in response to cocaine cues but not to appetitive control stimuli. Moreover, CCA also showed increased activation within the orbital frontal cortex (OFC) for cocaine cues relative to the appetitive stimuli during a hierarchical regression analysis. A negative association between subjective craving and activity in medial posterior cingulate gyrus (PCC) was also observed for CCA. CCA exhibited increased resting state correlation (positive) between cue-processing seed regions (OFC and ventral striatum), and negative connectivity between cue-processing regions and PCC/precuneus. These alterations in fcMRI may partially explain the neural basis of increased drug cue salience in CCA.

Head Injury or Head Motion? Assessment and Quantification of Motion Artifacts in Diffusion Tensor Imaging Studies

The relationship between head motion and diffusion values such as fractional anisotropy (FA) and mean diffusivity (MD) is currently not well understood. Simulation studies suggest that head motion may introduce either a positive or negative bias, but this has not been quantified in clinical studies. Moreover, alternative measures for removing bias as result of head motion, such as the removal of problematic gradients, has been suggested but not carefully evaluated. The current study examined the impact of head motion on FA and MD across three common pipelines (tract‐based spatial statistics, voxelwise, and region of interest analyses) and determined the impact of removing diffusion weighted images. Our findings from a large cohort of healthy controls indicate that while head motion was associated with a positive bias for both FA and MD, the effect was greater for MD. The positive bias was observed across all three analysis pipelines and was present following established protocols for data processing, suggesting that current techniques (i.e., correction of both image and gradient table) for removing motion bias are likely insufficient. However, the removal of images with gross artifacts did not fundamentally change the relationship between motion and DTI scalar values. In addition, Monte Carlo simulations suggested that the random removal of images increases the bias and reduces the precision of both FA and MD. Finally, we provide an example of how head motion can be quantified across different neuropsychiatric populations, which should be implemented as part of any diffusion tensor imaging quality assurance protocol. Hum Brain Mapp, 2012.

Dual and Opposing Modulatory Effects of Serotonin on Crayfish Lateral Giant Escape Command Neurons

Serotonin modulates afferent synaptic transmission to the lateral giant neurons of crayfish, which are command neurons for escape behavior. Low concentrations, or high concentrations reached gradually, are facilitatory, whereas high concentrations reached rapidly are inhibitory. The modulatory effects rapidly reverse after brief periods of application, whereas longer periods of application are followed by facilitation that persists for hours. These effects of serotonin can be reproduced by models that involve multiple interacting intracellular signaling systems that are each stimulated by serotonin. The dependence of the neuromodulatory effect on dose, rate, and duration of modulator application may be relevant to understanding the effects of natural neuromodulation on behavior and cognition and to the design of drug therapies.

Multisystem Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

Modeling conflict and error in the medial frontal cortex.

Despite intensive study, the role of the dorsal medial frontal cortex (dMFC) in error monitoring and conflict processing remains actively debated. The current experiment manipulated conflict type (stimulus conflict only or stimulus and response selection conflict) and utilized a novel modeling approach to isolate error and conflict variance during a multimodal numeric Stroop task. Specifically, hemodynamic response functions resulting from two statistical models that either included or isolated variance arising from relatively few error trials were directly contrasted. Twenty‐four participants completed the task while undergoing event‐related functional magnetic resonance imaging on a 1.5‐Tesla scanner. Response times monotonically increased based on the presence of pure stimulus or stimulus and response selection conflict. Functional results indicated that dMFC activity was present during trials requiring response selection and inhibition of competing motor responses, but absent during trials involving pure stimulus conflict. A comparison of the different statistical models suggested that relatively few error trials contributed to a disproportionate amount of variance (i.e., activity) throughout the dMFC, but particularly within the rostral anterior cingulate gyrus (rACC). Finally, functional connectivity analyses indicated that an empirically derived seed in the dorsal ACC/pre‐SMA exhibited strong connectivity (i.e., positive correlation) with prefrontal and inferior parietal cortex but was anti‐correlated with the default‐mode network. An empirically derived seed from the rACC exhibited the opposite pattern, suggesting that sub‐regions of the dMFC exhibit different connectivity patterns with other large scale networks implicated in internal mentations such as daydreaming (default‐mode) versus the execution of top‐down attentional control (fronto‐parietal). Hum Brain Mapp, 2012.

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder.

Significance Characterizing the abnormalities in sleep and activity that are associated with bipolar disorder (BP) and identifying their causation are key milestones in unraveling the biological underpinnings of this severe and highly prevalent disorder. We have conducted the first systematic evaluation of sleep and activity phenotypes in pedigrees that include multiple BP-affected members. By delineating specific sleep and activity measures that are significantly heritable in these families, and those whose variation correlated with the BP status of their members, and by determining the chromosomal position of loci contributing to many of these traits, we have taken the first step toward discovery of causative genetic variants. These variants, in turn, could provide clues to new approaches for both preventing and treating BP. Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non–BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I–associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non–BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.

Hyperactivation of the cognitive control network in cocaine use disorders during a multisensory Stroop task

BACKGROUND It has been suggested that individuals with cocaine use disorders (chronic cocaine abusers, CCA) have impairments in cognitive control, which likely contribute to impairments in decision making around drug use and relapse. However, deficits in cognitive control have currently only been studied under conditions of unisensory stimulation, which may not be reflective of more realistic multisensory drug cues. METHODS The current study employed functional magnetic resonance imaging (fMRI) to measure neuronal activity during a multisensory numeric Stroop task. RESULTS Despite few differences in reaction time, recently abstinent CCA (N=14) exhibited increased activation in prefrontal cortex, striatum and thalamus during cognitive control relative to a group of carefully matched controls (N=16). Importantly, these neuronal differences were relatively robust in classifying patients from controls (approximately 90% accuracy) and evident during conditions of both low (slow stimulus presentation rate) and relatively high (faster stimulus presentation rate) cognitive demand. In addition, CCA also failed to deactivate the default-mode network during high frequency visual trials. CONCLUSIONS In summary, current results indicate compensatory activation within the cognitive control network in recently abstinent CCA to achieve similar levels of behavioral performance.

Brain structure–function associations in multi-generational families genetically enriched for bipolar disorder

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.

The Subjective Experience of Pain: An FMRI Study of Percept-Related Models and Functional Connectivity

OBJECTIVE Previous work suggests that the perception of pain is subjective and dependent on individual differences in physiological, emotional, and cognitive states. Functional magnetic resonance imaging (FMRI) studies have used both stimulus-related (nociceptive properties) and percept-related (subjective experience of pain) models to identify the brain networks associated with pain. Our objective was to identify the network involved in processing subjective pain during cold stimuli. METHODS The current FMRI study directly contrasted a stimulus-related model with a percept-related model during blocks of cold pain stimuli in healthy adults. Specifically, neuronal activation was modelled as a function of changes in stimulus intensity vs as a function of increasing/decreasing levels of subjective pain corresponding to changes in pain ratings. In addition, functional connectivity analyses were conducted to examine intrinsic correlations between three proposed subnetworks (sensory/discriminative, affective/motivational, and cognitive/evaluative) involved in pain processing. RESULTS The percept-related model captured more extensive activation than the stimulus-related model and demonstrated an association between higher subjective pain and activation in expected cortical (dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, insula, dorsal anterior cingulate cortex [dACC] extending into pre-supplementary motor area) and subcortical (thalamus, striatum) areas. Moreover, connectivity results supported the posited roles of dACC and insula as key relay sites during neural processing of subjective pain. In particular, anterior insula appeared to link sensory/discriminative regions with regions in the other subnetworks, and dACC appeared to serve as a hub for affective/motivational, cognitive/evaluative, and motor subnetworks. CONCLUSIONS Using a percept-related model, brain regions involved in the processing of subjective pain during the application of cold stimuli were identified. Connectivity analyses identified linkages between key subnetworks involved in processing subjective pain.

An fMRI study of multimodal selective attention in schizophrenia

BACKGROUND Studies have produced conflicting evidence regarding whether cognitive control deficits in patients with schizophrenia result from dysfunction within the cognitive control network (CCN; top-down) and/or unisensory cortex (bottom-up). AIMS To investigate CCN and sensory cortex involvement during multisensory cognitive control in patients with schizophrenia. METHOD Patients with schizophrenia and healthy controls underwent functional magnetic resonance imaging while performing a multisensory Stroop task involving auditory and visual distracters. RESULTS Patients with schizophrenia exhibited an overall pattern of response slowing, and these behavioural deficits were associated with a pattern of patient hyperactivation within auditory, sensorimotor and posterior parietal cortex. In contrast, there were no group differences in functional activation within prefrontal nodes of the CCN, with small effect sizes observed (incongruent-congruent trials). Patients with schizophrenia also failed to upregulate auditory cortex with concomitant increased attentional demands. CONCLUSIONS Results suggest a prominent role for dysfunction within auditory, sensorimotor and parietal areas relative to prefrontal CCN nodes during multisensory cognitive control.