Resting Hypoconnectivity of Theoretically Defined Addiction Networks during Early Abstinence Predicts Subsequent Relapse in Alcohol Use Disorder.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

Exploratory study of how Cognitive Multisensory Rehabilitation restores parietal operculum connectivity and improves upper limb movements in chronic stroke.

Cognitive Multisensory Rehabilitation (CMR) is a promising therapy for upper limb recovery in stroke, but the brain mechanisms are unknown. We previously demonstrated that the parietal operculum (parts OP1/OP4) is activated with CMR exercises. In this exploratory study, we assessed the baseline difference between OP1/OP4 functional connectivity (FC) at rest in stroke versus healthy adults to then explore whether CMR affects OP1/OP4 connectivity and sensorimotor recovery after stroke. We recruited 8 adults with chronic stroke and left hemiplegia/paresis and 22 healthy adults. Resting-state FC with the OP1/OP4 region-of-interest in the affected hemisphere was analysed before and after 6 weeks of CMR. We evaluated sensorimotor function and activities of daily life pre- and post-CMR, and at 1-year post-CMR. At baseline, we found decreased FC between the right OP1/OP4 and 34 areas distributed across all lobes in stroke versus healthy adults. After CMR, only four areas had decreased FC compared to healthy adults. Compared to baseline (pre-CMR), participants improved on motor function (MESUPES arm p = 0.02; MESUPES hand p = 0.03; MESUPES total score p = 0.006); on stereognosis (p = 0.03); and on the Frenchay Activities Index (p = 0.03) at post-CMR and at 1-year follow-up. These results suggest enhanced sensorimotor recovery post-stroke after CMR. Our results justify larger-scale studies.

Resting-state thalamic dysconnectivity in schizophrenia and relationships with symptoms.

BACKGROUND: Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities. METHOD: Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined. RESULTS: HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior. CONCLUSIONS: Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.

Decreased hemispheric connectivity and decreased intra- and inter- hemisphere asymmetry of resting state functional network connectivity in schizophrenia.

Many studies have shown that schizophrenia patients have aberrant functional network connectivity (FNC) among brain regions, suggesting schizophrenia manifests with significantly diminished (in majority of the cases) connectivity. Schizophrenia is also associated with a lack of hemispheric lateralization. Hoptman et al. (2012) reported lower inter-hemispheric connectivity in schizophrenia patients compared to controls using voxel-mirrored homotopic connectivity. In this study, we merge these two points of views together using a group independent component analysis (gICA)-based approach to generate hemisphere-specific timecourses and calculate intra-hemisphere and inter-hemisphere FNC on a resting state fMRI dataset consisting of age- and gender-balanced 151 schizophrenia patients and 163 healthy controls. We analyzed the group differences between patients and healthy controls in each type of FNC measures along with age and gender effects. The results reveal that FNC in schizophrenia patients shows less hemispheric asymmetry compared to that of the healthy controls. We also found a decrease in connectivity in all FNC types such as intra-left (L_FNC), intra-right (R_FNC) and inter-hemisphere (Inter_FNC) in the schizophrenia patients relative to healthy controls, but general patterns of connectivity were preserved in patients. Analyses of age and gender effects yielded results similar to those reported in whole brain FNC studies.

The Effect of Vascular Neuropathology on Late-life Cognition: Results from the SMART Project.

BACKGROUND: Cerebral vascular pathology may contribute to cognitive decline experienced by some elderly near death. Given evidence for mixed neuropathologies in advanced age, preventing or reducing cerebrovascular burden in late life may be beneficial. OBJECTIVE: To correlate measures of cerebral vascular pathology with cognitive trajectories. SETTING: Observational study. PARTICIPANTS: A cohort of 2,274 individuals who came to autopsy at a mean age of 89.3 years and 82 percent of whom had at least two cognitive assessments within the last six years of life was compiled from six centers conducting longitudinal studies. MEASUREMENTS: For each cognitive domain: immediate and delayed memory, language, and naming, three trajectories were examined: good, intermediate, and poor cognition. The probability of a participant belonging to each trajectory was associated with measures of cerebral vascular pathology after adjustment for demographics, APOE, and Alzheimer neuropathology. RESULTS: A large proportion of the cohort (72-94%) experienced good or intermediate cognition in the four domains examined. The presence of arteriolosclerosis and the presence of lacunar infarcts doubled the odds of belonging to the poor cognitive trajectory for language when compared to the good trajectory. The presence of lacunar infarcts increased the odds of an intermediate or poor trajectory for immediate and delayed recall while the presence of large artery infarcts increased the odds of poor trajectories for all four cognitive domains examined. Microinfarcts and cerebral amyloid angiopathy had little effect on the trajectories. CONCLUSION: Indicators of cerebral vascular pathology act differently on late life cognition.

The Statistical Modeling of Aging and Risk of Transition Project: Data Collection and Harmonization Across 11 Longitudinal Cohort Studies of Aging, Cognition, and Dementia.

Longitudinal cognitive trajectories and other factors associated with mixed neuropathologies (such as Alzheimer's disease with co-occurring cerebrovascular disease) remain incompletely understood, despite being the rule and not the exception in older populations. The Statistical Modeling of Aging and Risk of Transition study (SMART) is a consortium of 11 different high-quality longitudinal studies of aging and cognition (N=11,541 participants) established for the purpose of characterizing risk and protective factors associated with subtypes of age-associated mixed neuropathologies (N=3,001 autopsies). While brain donation was not required for participation in all SMART cohorts, most achieved substantial autopsy rates (i.e., > 50%). Moreover, the studies comprising SMART have large numbers of participants who were followed from intact cognition and transitioned to cognitive impairment and dementia, as well as participants who remained cognitively intact until death. These data provide an exciting opportunity to apply sophisticated statistical methods, like Markov processes, that require large, well-characterized samples. Thus, SMART will serve as an important resource for the field of mixed dementia epidemiology and neuropathology.

Default network connectivity as a vulnerability marker for obsessive compulsive disorder.

BACKGROUND: Aberrant functional connectivity within the default network is generally assumed to be involved in the pathophysiology of obsessive compulsive disorder (OCD); however, the genetic risk of default network connectivity in OCD remains largely unknown. METHOD: Here, we systematically investigated default network connectivity in 15 OCD patients, 15 paired unaffected siblings and 28 healthy controls. We sought to examine the profiles of default network connectivity in OCD patients and their siblings, exploring the correlation between abnormal default network connectivity and genetic risk for this population. RESULTS: Compared with healthy controls, OCD patients exhibited reduced strength of default network functional connectivity with the posterior cingulate cortex (PCC), and increased functional connectivity in the right inferior frontal lobe, insula, superior parietal cortex and superior temporal cortex, while their unaffected first-degree siblings only showed reduced local connectivity in the PCC. CONCLUSIONS: These findings suggest that the disruptions of default network functional connectivity might be associated with family history of OCD. The decreased default network connectivity in both OCD patients and their unaffected siblings may serve as a potential marker of OCD.

Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study.

BACKGROUND: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

Neuropsychiatric applications of DTI - a review.

Psychiatric disorders are common throughout the world and are a leading cause of disability. There is a growing appreciation of the importance of connectivity to brain function. Disruption of this connectivity can result in brain dysfunction manifested in impaired cognitive functioning and the development of clinical symptoms. White matter forms the basis of anatomical connectivity. Diffusion tensor imaging (DTI) is a useful tool for examining and quantifying white matter microstructure. Clinical research studies in alcoholism, HIV-1 infection, geriatric depression and schizophrenia using DTI have revealed abnormalities in white matter microstructure. The use of complementary imaging methods may be helpful in further characterizing these abnormalities. Other psychiatric disorders may also have white matter involvement amenable to study with DTI. Advances in acquisition and analysis methods will be necessary to further advance work in this field. The study of animal models and postmortem tissue may be helpful in elucidating the neurobiological underpinnings of abnormalities observed with DTI.

Structural brain abnormalities in patients with schizophrenia, epilepsy, and epilepsy with chronic interictal psychosis.

Chronic interictal psychotic syndromes, often resembling schizophrenia, develop in some patients with epilepsy. Although widespread brain abnormalities are recognized as characteristic of schizophrenia, prevailing but controversial hypotheses on the co-occurrence of epilepsy and psychosis implicate left temporal lobe pathology. In this study, quantitative MRI methods were used to address the regional specificity of structural brain abnormalities in patients with epilepsy plus chronic interictal psychosis (E+PSY, n=9) relative to three comparison groups: unilateral temporal lobe epilepsy without chronic psychosis (TLE, n=18), schizophrenia (SCZ, n=46), and healthy control subjects (HC, n=57). Brain measures, derived from a coronal spin-echo MRI sequence, were adjusted for age and cerebral volume. Relative to HC, all patient groups had ventricular enlargement and smaller temporal lobe, frontoparietal, and superior temporal gyrus gray matter volumes, with the extent of these abnormalities greatest in E+PSY. Only TLE had temporal lobe white matter deficits, as well as smaller hippocampi, which were ipsilateral to the seizure focus. Structural brain abnormalities in E+PSY are not restricted to the left temporal lobe. The confluence of cortical gray matter deficits in E+PSY and SCZ suggests salience to chronic psychosis.

Remote memory for public figures in Alzheimer's disease: relationships to regional cortical and limbic brain volumes.

This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.

White matter abnormalities in HIV-1 infection: a diffusion tensor imaging study.

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been found to be particularly prominent in the advanced stages of the disease. The purpose of this study was to determine whether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo, using diffusion tensor imaging (DTI). DTI is a magnetic resonance imaging (MRI) technique that is uniquely suited for the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. The two groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobes and internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed proton density, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle white matter disruptions in HIV-1 disease.

Equivalent disruption of regional white matter microstructure in ageing healthy men and women.

Diffusion tensor imaging was used to measure regional differences in brain white matter microstructure (intravoxel coherence) and macrostructure (intervoxel coherence) and age-related differences between men and women. Neuropsychiatrically healthy men and women, spanning the adult age range, showed the same pattern of variation in regional white matter coherence. The greatest coherence measured was in corpus callosum, where commissural fibers have one primary orientation, lower in the centrum semiovale, where fibers cross from multiple axes, and lowest in pericallosal areas, where fibers weave and interstitial fluid commonly pools. Age-related declines in intravoxel coherence was equally strong and strikingly similar in men and women, with evidence for greater age-dependent deterioration in frontal than parietal regions. Degree of regional white matter coherence correlated with gait, balance, and interhemispheric transfer test scores.

Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study.

BACKGROUND: We sought to determine whether the brain dysmorphology previously observed cross-sectionally in people with schizophrenia progresses over time and whether such progression is related to the severity of the illness course. SUBJECTS AND METHODS: Men with chronic schizophrenia (n = 24) and control men (n = 25) received 2 brain magnetic resonance imaging scans, on average 4 years apart. Changes in brain volume were adjusted for head-repositioning error and expressed as slopes (cubic centimeters per year). Clinical course severity for the schizophrenic patients was assessed using the mean of time 1 and time 2 Brief Psychiatric Rating Scale (BPRS) scores and the percentage of time the patient was hospitalized during the interscan interval. RESULTS: Schizophrenic patients exhibited faster volume decline than control subjects in right frontal gray matter and bilateral posterior superior temporal gray matter, as well as faster cerebrospinal fluid volume expansion in right frontal sulci, left lateral ventricle, and bilateral prefrontal and posterior superior temporal sulci. Faster rates of frontal sulcal expansion were related to greater BPRS total and positive symptom scores and longer time hospitalized. Prefrontal gray matter decline and sulcal expansion were associated with greater BPRS negative symptom scores and longer time hospitalized. Temporal lobe gray matter decline was associated with greater BPRS total and negative symptom scores. CONCLUSIONS: This controlled study revealed that patients with chronic schizophrenia exhibited accelerated frontotemporal cortical gray matter decline and cortical sulcal and lateral ventricular expansion. Further, greater clinical severity was associated with faster rates of frontotemporal brain volume changes. These observations are consistent with a progressive pathophysiological process but need to be replicated in a larger sample.

Steady flow visualization in a rigid model of the aortic bifurcation: application to atherosclerosis.

Hemodynamics have long been implicated in atherogenesis. The studiesreported here seek to explain the mechanisms for the formation ofatherosclerotic plaque in an aortic bifurcation. Flow studies were made ina model constructed from plexiglass to represent an aortic bifurcation. Under steady flow conditions at inflow Reynolds numbers of 80-1250,the streamline flow patterns and the boundary layer separation zones wereinvestigated in relation to the location of atherosclerotic plaques clinicallyfound at regions in the human aortic bifurcation. The streamline flowswere visualized by a slow injection of dye over the cross section of the tubeentrance and along the tube walls. The studies revealed a complex flowfield where secondary flows, induced by the centrifugal and viscous forces,cause the fluid to move towards the inner walls of the aortic bifurcation. The effect was more clearly seen with increasing Reynolds number. Boundary layer separation zones were observed to occur at the outercorners of the branching. The nature of the separation zone formed wasfound to be dependent on Reynolds number. The residence time of fluidparticles within such a separation zone was estimated by measuring thewashout time of a bolus of dye injected at strategic locations along the tubewalls. The residence time was found to decrease exponentially withincreasing Reynolds number. These observations provide strong support forthe role of flow separation in the accumulation of LDL and plateletaggregation within the aortic bifurcation.

In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism.

BACKGROUND: Postmortem studies report degradation of brain white matter microstructure in chronic alcoholism, but until recently, in vivo neuroimaging could provide measurement only at a macrostructural level. The development of magnetic resonance diffusion tensor imaging (DTI) for clinical use offers a method for depicting and quantifying the diffusion properties of white matter expressed as intravoxel and intervoxel coherence of tracts and fibers. METHODS: This study used DTI to examine the intravoxel coherence measured as fractional anisotropy (FA) and intervoxel coherence (C) of white matter tracts of the genu and splenium of the corpus callosum and of the centrum semiovale in 15 detoxified alcoholic men and 31 nonalcoholic control subjects. Exploratory correlational analyses examined the relationships between regional DTI measures and tests of attention and working memory in the alcoholic patients. RESULTS: The alcoholic group had lower regional FA than the control group. C was lower in the alcoholics than controls in the splenium only. Working memory correlated positively with splenium FA, whereas attention correlated positively with genu C. CONCLUSIONS: These results provide in vivo evidence for disruption of white matter microstructure in alcoholism and suggest that interruption of white matter fiber coherence contributes to disturbance in attention and working memory in chronic alcoholism.

Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia.

BACKGROUND: It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities. METHOD: We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age. RESULTS: Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined. CONCLUSIONS: Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.

Cerebellar volume decline in normal aging, alcoholism, and Korsakoff's syndrome: relation to ataxia.

The authors used magnetic resonance imaging to measure gray and white matter volumes in cerebellar hemispheres and 4 vermian regions in 61 normal control (NC) men aged 23-72 years, 25 men with uncomplicated alcoholism (ALC), and 8 men and 1 woman with alcoholic Korsakoff s syndrome (KS). NC and ALC took quantitative gait and balance tests. Gray but not white matter volume declined with normal age in both hemispheres and anterior-superior vermis. ALC had gray but not white matter cerebellar hemisphere volume deficits, whereas KS had deficits in both tissue types. ALC and KS had gray and white matter volume deficits in anterior superior but not posterior inferior vermis. ALC had a 1 SD ataxia deficit, significantly and selectively correlated with white matter volume in anterior superior vermis. Regional distribution but not severity of cerebellar volume deficits is similar in alcoholic individuals whether or not complicated by KS and relates to ataxia.

Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging.

Echo planar (EP) diffusion tensor imaging (DTI) permits in vivo identification of the orientation and coherence of brain white matter tracts but suffers from field inhomogeneity-induced geometric distortion. To reduce spatial distortion, polynomial warping corrections were applied and the effects tested on measures of fractional anisotropy (FA) in the genu and splenium of corpus callosum. Implementation entailed spatially warping EP images obtained without diffusion weighting (b = 0) to long-echo T(2)-weighted fast spin echo images, collected for anatomical delineation, tissue segmentation, and coregistration with the diffusion images. Using the optimal warping procedure (third-order polynomial), the effects of age on FA and a quantitative measure of intervoxel coherence (C) in the genu, splenium, centrum semiovale, and frontal and parietal pericallosal white matter were examined in 31 healthy men (23-76 years). FA declined significantly with age in all regions except the splenium, whereas intervoxel coherence positively correlated with age in the genu. Magn Reson Med 44:259-268, 2000.

Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: relationships to changes in brain structure.

Chronic alcoholism is associated with cognitive and motor deficits, and there is evidence for reversibility with sobriety. Alcoholic men were examined after 1 month of sobriety and 2 to 12 months later with cognitive and motor tests and magnetic resonance imaging. In this naturalistic study, 20 alcoholic participants had abstained and 22 had resumed drinking at retesting. Abstainers sustained greater improvement than relapsers on tests of delayed recall of drawings, visuospatial function, attention, gait, and balance. Shrinkage in 3rd ventricle volume across all participants significantly correlated with improvement in nonverbal short-term memory. Additional brain structure-function relationships, most involving short-term memory, were observed when analyses were restricted to alcoholic men who had maintained complete abstinence, were light relapsers for at least 3 months, or had consumed no more than 10 drinks prior to follow-up testing. Thus, alcoholic men who maintain abstinence can show substantial functional improvement that is related to improvement in brain structure condition.