MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Sharing pain and relief: neural correlates of physicians during treatment of patients.

Patient-physician interactions significantly contribute to placebo effects and clinical outcomes. While the neural correlates of placebo responses have been studied in patients, the neurobiology of the clinician during treatment is unknown. This study investigated physicians' brain activations during patient-physician interaction while the patient was experiencing pain, including a 'treatment', 'no-treatment' and 'control' condition. Here, we demonstrate that physicians activated brain regions previously implicated in expectancy for pain-relief and increased attention during treatment of patients, including the right ventrolateral and dorsolateral prefrontal cortices. The physician's ability to take the patients' perspective correlated with increased brain activations in the rostral anterior cingulate cortex, a region that has been associated with processing of reward and subjective value. We suggest that physician treatment involves neural representations of treatment expectation, reward processing and empathy, paired with increased activation in attention-related structures. Our findings further the understanding of the neural representations associated with reciprocal interactions between clinicians and patients; a hallmark for successful treatment outcomes.

Striatal function in relation to negative symptoms in schizophrenia.

BACKGROUND: Previous studies have suggested that motivational aspects of executive functioning, which may be disrupted in schizophrenia patients with negative symptoms, are mediated in part by the striatum. Negative symptoms have been linked to impaired recruitment of both the striatum and the dorsolateral prefrontal cortex (DLPFC). Here we tested the hypothesis that negative symptoms are associated primarily with striatal dysfunction, using functional magnetic resonance imaging (fMRI). METHOD: Working-memory load-dependent activation and gray matter volumes of the striatum and DLPFC were measured using a region-of-interest (ROI) approach, in 147 schizophrenia patients and 160 healthy controls. In addition to testing for a linear relationships between striatal function and negative symptoms, we chose a second, categorical analytic strategy in which we compared three demographically and behaviorally matched subgroups: patients with a high burden of negative symptoms, patients with minimal negative symptoms, and healthy subjects. RESULTS: There were no differences in striatal response magnitudes between schizophrenia patients and healthy controls, but right DLPFC activity was higher in patients than in controls. Negative symptoms were inversely associated with striatal, but not DLPFC, activity. In addition, patients with a high burden of negative symptoms exhibited significantly lower bilateral striatal, but not DLPFC, activation than schizophrenia patients with minimal negative symptoms. Working memory performance, antipsychotic exposure and changes in gray matter volumes did not account for these differences. CONCLUSIONS: These data provide further evidence for a robust association between negative symptoms and diminished striatal activity. Future work will determine whether low striatal activity in schizophrenia patients could serve as a reliable biomarker for negative symptoms.

Antipsychotic dose and diminished neural modulation: a multi-site fMRI study.

BACKGROUND: The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. METHODS: Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. RESULTS: Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho=-0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). CONCLUSION: The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.

Test-retest reliability of a functional MRI working memory paradigm in normal and schizophrenic subjects.

OBJECTIVE: Repeated functional magnetic resonance imaging (fMRI) studies of schizophrenic subjects may identify brain activity changes in response to interventions. To interpret the findings, however, it is crucial to know the test-retest reliability of the measures used. METHOD: The authors scanned seven normal subjects and seven schizophrenic subjects on two occasions during performance of a working memory task. They quantified the reliability of task performance and brain activation. RESULTS: In both groups, task performance was reliable, and all a priori regions were activated in group-averaged test and retest data. In individual schizophrenic subjects, however, indices of cognitive activation were not reliable across sessions. Normal subjects showed reasonable reliability of activation. CONCLUSIONS: Even given reliable task performance, stable clinical status, and a stable pattern of group-averaged activation, individual subjects showed unreliable brain activation. This suggests that repeated fMRI studies of schizophrenia should control for sources of variation, both artifactual and intrinsic.

Clinical outcomes following cocaine infusion in nontreatment-seeking individuals with cocaine dependence.

BACKGROUND: In this study we explored if laboratory-based cocaine administration to human subjects was associated with long-term adverse outcomes. METHODS: Twenty-one non--reatment seeking individuals with cocaine dependence were evaluated at baseline and again 5 and 10 months following cocaine infusion in a brain imaging study. Outcomes included computer-driven multidimensional clinical assessments and radioimmunoassay of hair. For comparison, identical data were collected from 19 cocaine-dependent subjects who did not receive the infusion. RESULTS: The infused and noninfused groups did not differ on frequency of cocaine use (corroborated by radioimmunoassay of hair), Addiction Severity Index drug composite score, or Hamilton Rating Scale for Depression score at both follow-up time points. In a time-related trend analysis, both groups showed significant reductions in frequency of cocaine use. CONCLUSIONS: Laboratory-based cocaine administration can be a safe paradigm even in individuals who are not engaged in treatment.

The validity of self-reported drug use in non-treatment seeking individuals with cocaine dependence: correlation with biochemical assays.

Accurate estimate of drug exposure plays an important role in studies of the neurobiology of drug dependence. The validity of self-reported drug use by subjects participating in such studies has not been well established. This study examined the relationship between self-reported drug use and biological markers in 18 non-treatment-seeking cocaine-dependent individuals participating in research on the effects of cocaine on the brain. A significant relationship was found between self-reported frequency of cocaine use and hair cocaine concentration. Frequency of alcohol use correlated significantly with plasma carbohydrate-deficient transferrin and aspartate aminotransferase levels. These results suggest that self-reported substance use in non-treatment seeking research subjects is generally valid.

Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance.

BACKGROUND: Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (Manoach et al 1999b). We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM. METHODS: We examined regional brain activation in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data. RESULTS: Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation, and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group. CONCLUSIONS: Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM. Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits.

Functional brain mapping of the relaxation response and meditation.

Meditation is a conscious mental process that induces a set of integrated physiologic changes termed the relaxation response. Functional magnetic resonance imaging (fMRI) was used to identify and characterize the brain regions that are active during a simple form of meditation. Significant (p<10(-7)) signal increases were observed in the group-averaged data in the dorsolateral prefrontal and parietal cortices, hippocampus/parahippocampus, temporal lobe, pregenual anterior cingulate cortex, striatum, and pre- and post-central gyri during meditation. Global fMRI signal decreases were also noted, although these were probably secondary to cardiorespiratory changes that often accompany meditation. The results indicate that the practice of meditation activates neural structures involved in attention and control of the autonomic nervous system.

Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects.

Acupuncture, an ancient therapeutic technique, is emerging as an important modality of complementary medicine in the United States. The use and efficacy of acupuncture treatment are not yet widely accepted in Western scientific and medical communities. Demonstration of regionally specific, quantifiable acupuncture effects on relevant structures of the human brain would facilitate acceptance and integration of this therapeutic modality into the practice of modern medicine. Research with animal models of acupuncture indicates that many of the beneficial effects may be mediated at the subcortical level in the brain. We used functional magnetic resonance imaging (fMRI) to investigate the effects of acupuncture in normal subjects and to provide a foundation for future studies on mechanisms of acupuncture action in therapeutic interventions. Acupuncture needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced prominent decreases of fMRI signals in the nucleus accumbens, amygdala, hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11 subjects who experienced acupuncture sensation. In marked contrast, signal increases were observed primarily in the somatosensory cortex. The two subjects who experienced pain instead of acupuncture sensation exhibited signal increases instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen, anterior thalamus, and posterior insula. Superficial tactile stimulation to the same area elicited signal increases in the somatosensory cortex as expected, but no signal decreases in the deep structures. These preliminary results suggest that acupuncture needle manipulation modulates the activity of the limbic system and subcortical structures. We hypothesize that modulation of subcortical structures may be an important mechanism by which acupuncture exerts its complex multisystem effects.

Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence.

The hypothalamic-pituitary-adrenal (HPA) axis plays a role in cocaine dependence and major depressive disorder. The authors examined the correlation between baseline depressive symptomatology and pituitary-adrenal axis activation induced by acute cocaine challenge. Twelve patients with cocaine dependence were administered an iv bolus of cocaine (0.6 mg/kg) and their plasma was assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. Depressive symptomatology was assessed with total Hamilton rating scale for depression (HRSD) scores and its vegetative and cognitive superfactors. Cocaine produced a mean increase from baseline of 261% for ACTH and 73% for cortisol plasma levels. Changes in ACTH (r=0.69) and cortisol (r=0.59) were positively and significantly correlated with total HRSD scores and its vegetative, but not cognitive, factor symptom cluster. These results suggest that the HPA axis may be involved in affective disturbances associated with the use of cocaine. Implications of these data for the pathophysiology of cocaine dependence are discussed.

Acupuncture: pain management coupled to immune stimulation.

The phenomenon of acupuncture is both complex and dynamic. Recent information demonstrates that acupuncture may exert its actions on pain and immune processes. The coupling of these two systems occurs via common signaling molecules, i.e., opioid peptides. In this regard, we surmise that opioid activation leads to the processing of opioid peptides from their precursor, proenkephalin, and the simultaneous release of antibacterial peptides contained within the precursor as well. Thus, central nervous system pain circuits may be coupled to immune enhancement. Furthermore, acupuncture needle manipulation elicited signal increases bilaterally in the region of the primary and secondary somatosensory corticies in human brain as determined by magnetic resonance imaging. The maps reveal marked signal decreases bilaterally in multiple limbic and deep gray structures including the nucleus accumbens, amygdala, hypothalamus, hippocampus, and ventral tegmental area. Taken together, we surmise a major central nervous system pathway as well as local pain and immune modulation during acupuncture.

Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects.

The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (i.v.) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan sequences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg i.v. over 30 seconds) increased heart rate and mean blood pressure and decreased end tidal carbon dioxide (CO2). All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged after saline infusion (-2.4 +/- 6.5%) but decreased (-14.1 +/- 8.5%) after cocaine infusion (n = 8, P < 0.01). No decreases were detected in white matter, nor were changes found comparing BOLD signal intensity in cortical gray matter immediately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small (14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reliably.

Acute effects of cocaine on human brain activity and emotion.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.