Mode of Anisotropy Reveals Global Diffusion Alterations in Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.

Resting-state functional and structural connectivity within an insula-amygdala route specifically index state and trait anxiety.

BACKGROUND: Conjoint activity of the insula and amygdala has frequently been reported during emotional stimulation in general and in anxiety-related contexts in particular. However, direct connectivity between the insula and amygdala in this framework has received little attention so far. Studying whether inter-individual differences in anxiety reflect variation in insula-amygdala connectivity is a way to push forward the understanding of network-related aspects underlying anxious behavior. METHODS: To investigate functional and structural connectivity, we applied resting-state functional magnetic resonance imaging and diffusion tensor imaging in a group of 32 healthy subjects. Specific measures of connectivity between subregions of the insula and amygdala were related to subjects' anxiety levels. RESULTS: Resting-state functional connectivity between the anterior insula and the basolateral amygdala was strongly related to state anxiety, explaining 40% of behavioral variance across subjects. This was substantiated by applying tractography, yielding a relationship between trait anxiety and axial diffusivity for a direct pathway between anterior insula and basolateral amygdala. CONCLUSIONS: Our results indicate that anterior insula and basolateral amygdala constitute a network part that is prominently linked to anxiety. Within this route, state and trait behavioral impacts seem to be specifically linked to dynamic functional and more static structural neural aspects, respectively. Insula-amygdala resting-state functional connectivity can be assessed in an easy and straightforward way and has high potential to serve as a biomarker for anxiety.

Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder.

BACKGROUND: Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. METHODS: We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. RESULTS: The FA differed significantly (p<.05; corrected) among the three groups within the right temporal WM. Unaffected siblings had FA values that were intermediate to and significantly different from those of healthy volunteers and patients with BD (healthy control subjects>unaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. CONCLUSIONS: Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD.

Impaired inter-hemispheric integration in bipolar disorder revealed with brain network analyses.

BACKGROUND: This represents the first graph theory-based brain network analysis study in bipolar disorder, a chronic and disabling psychiatric disorder characterized by severe mood swings. Many imaging studies have investigated white matter in bipolar disorder, with results suggesting abnormal white matter structural integrity, particularly in the fronto-limbic and callosal systems. However, many inconsistencies remain in the literature, and no study to date has conducted brain network analyses with a graph-theoretic approach. METHODS: We acquired 64-direction diffusion-weighted magnetic resonance imaging on 25 euthymic bipolar I disorder subjects and 24 gender- and age-equivalent healthy subjects. White matter integrity measures including fractional anisotropy and mean diffusivity were compared in the whole brain. Additionally, structural connectivity matrices based on whole-brain deterministic tractography were constructed, followed by the computation of both global and local brain network measures. We also designed novel metrics to further probe inter-hemispheric integration. RESULTS: Network analyses revealed that the bipolar brain networks exhibited significantly longer characteristic path length, lower clustering coefficient, and lower global efficiency relative to those of control subjects. Further analyses revealed impaired inter-hemispheric but relatively preserved intra-hemispheric integration. These findings were supported by whole-brain white matter analyses that revealed significantly lower integrity in the corpus callosum in bipolar subjects. There were also abnormalities in nodal network measures in structures within the limbic system, especially the left hippocampus, the left lateral orbitofrontal cortex, and the bilateral isthmus cingulate. CONCLUSIONS: These results suggest abnormalities in structural network organization in bipolar disorder, particularly in inter-hemispheric integration and within the limbic system.

Right lateralized white matter abnormalities in first-episode, drug-naive paranoid schizophrenia.

Numerous studies in first-episode schizophrenia suggest the involvement of white matter (WM) abnormalities in multiple regions underlying the pathogenesis of this condition. However, there has never been a neuroimaging study in patients with first-episode, drug-naive paranoid schizophrenia by using tract-based spatial statistics (TBSS) method. Here, we used diffusion tensor imaging (DTI) with TBSS method to investigate the brain WM integrity in patients with first-episode, drug-naive paranoid schizophrenia. Twenty patients with first-episode, drug-naive paranoid schizophrenia and 26 healthy subjects matched with age, gender, and education level were scanned with DTI. An automated TBSS approach was employed to analyze the data. Voxel-wise statistics revealed that patients with paranoid schizophrenia had decreased fractional anisotropy (FA) values in the right superior longitudinal fasciculus (SLF) II, the right fornix, the right internal capsule, and the right external capsule compared to healthy subjects. Patients did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain regions and patient demographics and the severity of illness. Our findings suggest right-sided alterations of WM integrity in the WM tracts of cortical and subcortical regions may play an important role in the pathogenesis of paranoid schizophrenia.

Both projection and commissural pathways are disrupted in individuals with chronic stroke: investigating microstructural white matter correlates of motor recovery.

BACKGROUND: Complete recovery of motor function after stroke is rare with deficits persisting into the chronic phase of recovery. Diffusion tensor imaging (DTI) can evaluate relationships between white matter microstructure and motor function after stroke. The objective of this investigation was to characterize microstructural fiber integrity of motor and sensory regions of the corpus callosum (CC) and descending motor outputs of the posterior limb of the internal capsule (PLIC) in individuals with chronic stroke and evaluate the relationships between white matter integrity and motor function. RESULTS: Standardized measures of upper extremity motor function were measured in thirteen individuals with chronic stroke. Manual dexterity was assessed in thirteen healthy age-matched control participants. DTI scans were completed for each participant. Fractional anisotropy (FA) of a cross-section of sensory and motor regions of the CC and the PLIC bilaterally were quantified. Multivariate analysis of variance evaluated differences between stroke and healthy groups. Correlational analyses were conducted for measures of motor function and FA. The stroke group exhibited reduced FA in the sensory (p = 0.001) region of the CC, contra- (p = 0.032) and ipsilesional (p = 0.001) PLIC, but not the motor region of the CC (p = 0.236). In the stroke group, significant correlations between contralesional PLIC FA and level of physical impairment (p = 0.005), grip strength (p = 0.006) and hand dexterity (p = 0.036) were observed. CONCLUSIONS: Microstructural status of the sensory region of the CC is reduced in chronic stroke. Future work is needed to explore relationships between callosal sensorimotor fiber integrity and interhemispheric interactions post-stroke. In addition, contralesional primary motor output tract integrity is uniquely and closely associated with multiple dimensions of motor recovery in the chronic phase of stroke suggesting it may be an important biomarker of overall motor recovery.

Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression.

The medial forebrain bundle (MFB), a key structure of reward-seeking circuitry, remains inadequately characterized in humans despite its vast importance for emotional processing and development of addictions and depression. Using Diffusion Tensor Imaging Fiber Tracking (DTI FT) the authors describe potential converging ascending and descending MFB and anterior thalamic radiation (ATR) that may mediate major brain reward-seeking and punishment functions. Authors highlight novel connectivity, such as supero-lateral-branch MFB and ATR convergence, caudally as well as rostrally, in the anterior limb of the internal capsule and medial prefrontal cortex. These anatomical convergences may sustain a dynamic equilibrium between positive and negative affective states in human mood-regulation and its various disorders, especially evident in addictions and depression.

Axonal integrity predicts cortical reorganisation following cervical injury.

BACKGROUND: Traumatic spinal cord injury (SCI) leads to disruption of axonal architecture and macroscopic tissue loss with impaired information flow between the brain and spinal cord-the presumed basis of ensuing clinical impairment. OBJECTIVE: The authors used a clinically viable, multimodal MRI protocol to quantify the axonal integrity of the cranial corticospinal tract (CST) and to establish how microstructural white matter changes in the CST are related to cross-sectional spinal cord area and cortical reorganisation of the sensorimotor system in subjects with traumatic SCI. METHODS: Nine volunteers with cervical injuries resulting in bilateral motor impairment and 14 control subjects were studied. The authors used diffusion tensor imaging to assess white matter integrity in the CST, T1-weighted imaging to measure cross-sectional spinal cord area and functional MRI to compare motor task-related brain activations. The relationships among microstructural, macrostructural and functional measures were assessed using regression analyses. Results Diffusion tensor imaging revealed significant differences in the CST of SCI subjects-compared with controls-in the pyramids, the internal capsule, the cerebral peduncle and the hand area. The microstructural white matter changes observed in the left pyramid predicted increased task-related responses in the left M1 leg area, while changes in the cerebral peduncle were predicted by reduced cord area. CONCLUSION: The observed microstructural changes suggest trauma-related axonal degeneration and demyelination, which are related to cortical motor reorganisation and macrostructure. The extent of these changes may reflect the plasticity of motor pathways associated with cortical reorganisation. This clinically viable multimodal imaging approach is therefore appropriate for monitoring degeneration of central pathways and the evaluation of treatments targeting axonal repair in SCI.

Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity.

Remodeling of neuronal structures and networks is believed to significantly contribute to (partial) restoration of functions after stroke. However, it has been unclear to what extent the brain reorganizes and how this correlates with functional recovery in relation to stroke severity. We applied serial resting-state functional MRI and diffusion tensor imaging together with behavioral testing to relate longitudinal modifications in functional and structural connectivity of the sensorimotor neuronal network to changes in sensorimotor function after unilateral stroke in rats. We found that gradual improvement of functions is associated with wide-ranging changes in functional and structural connectivity within bilateral neuronal networks, particularly after large stroke. Both after medium and large stroke, brain reorganization eventually leads to (partial) normalization of neuronal signal synchronization within the affected sensorimotor cortical network (intraregional signal coherence), as well as between the affected and unaffected sensorimotor cortices (interhemispheric functional connectivity). Furthermore, the bilateral network configuration shifts from subacutely increased "small-worldness," possibly reflective of initial excessive neuronal clustering and wiring, toward a baseline small-world topology, optimal for global information transfer and local processing, at chronic stages. Cortical network remodeling was accompanied by recovery of initially disrupted structural integrity in corticospinal tract regions, which correlated positively with retrieval of sensorimotor functions. Our study demonstrates that the degree of functional recovery after stroke is associated with the extent of preservation or restoration of ipsilesional corticospinal tracts in combination with reinstatement of interhemispheric neuronal signal synchronization and normalization of small-world cortical network organization.

Broad disruption of brain white matter microstructure and relationship with neuropsychological performance in male patients with severe alcohol dependence.

AIMS: In the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance. METHODS: Twenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated. RESULTS: Performance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas. CONCLUSION: These findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA.

Reduced left uncinate fasciculus fractional anisotropy in deficit schizophrenia but not in non-deficit schizophrenia.

AIMS: Schizophrenia is a psychiatric disorder manifesting with heterogeneous symptom clusters and clinical presentations. The deficit syndrome is the condition defined by the existence of primarily negative symptoms, and patients with the deficit syndrome differ from non-deficit patients on measures of brain structure and function. In the current study, by using diffusion tensor imaging (DTI), we investigated the frontotemporal connectivity that is hypothesized to differ between deficit and non-deficit schizophrenia. METHODS: Twenty-nine patients and 17 healthy controls were included in the study. The patients had deficit (n = 11) or non-deficit (n = 18) schizophrenia and they were evaluated clinically with the Schedule for Deficit Syndrome (SDS) and Positive and Negative Syndrome Scale (PANSS). Diffusion-based images were obtained with a 1.5T Siemens Magnetic Resonance Imaging machine and analyses were carried out with Functional Magnetic Resonance Imaging of the Brain Library Software - Diffusion tool box software. RESULTS: The fractional anisotropy values in the left uncinate fasciculus of schizophrenia patients with the deficit syndrome were lower than those of non-deficit patients and the controls. There were no differences between non-deficit schizophrenia patients and controls. CONCLUSION: These findings provide evidence of left uncinate fasciculus damage resulting in disrupted communication between orbitofrontal prefrontal areas and temporal areas in deficit schizophrenia patients.

How we remember the stuff that dreams are made of: neurobiological approaches to the brain mechanisms of dream recall.

Intrinsic and historical weaknesses delayed the spread of a sound neurobiological investigation on dreaming. Nevertheless, recent independent findings confirm the hypothesis that the neurophysiological mechanisms of encoding and recall of episodic memories are largely comparable across wakefulness and sleep. Brain lesion and neuroimaging studies converge in indicating that temporo-parieto-occipital junction and ventromesial prefrontal cortex play a crucial role in dream recall. Morphoanatomical measurements disclose some direct relations between volumetric and ultrastructural measures of the hippocampus-amygdala on the one hand, and some specific qualitative features of dreaming on the other. Intracranial recordings of epileptic patients also provide support for the notion that hippocampal nuclei mediate memory formation during sleep as well as in wakefulness. Finally, surface EEG studies showed that sleep cortical oscillations associated to a successful dream recall are the same involved in encoding and recall of episodic memories during wakefulness. Although preliminary, these converging pieces of evidence strengthen the general view that the neurophysiological mechanisms underlying episodic/declarative memory formation may be the same across different states of consciousness.

Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia.

The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age- and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.

Voxel based morphometric and diffusion tensor imaging analysis in male bipolar patients with first-episode mania.

OBJECTIVES: Structural abnormality of both gray and white matter has been detected in patients with bipolar disorder (BD). But results were greatly inconsistent across studies which were most likely attributed to heterogeneous populations as well as processing techniques. The present study aimed to investigate brain structural and microstructural alterations in a relative homogenous sample of bipolar mania. METHODS: 3D T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were conducted in 18 patients with BD and 27 healthy volunteers. Gray matter (GM) and white matter (WM) differences were evaluated using voxel-based morphometry (VBM) and voxel-based analysis of fractional anisotropy (FA) maps derived from DTI, respectively. RESULTS: Patients with BD had a larger volume of GM in the left thalamus and bilateral basal ganglia, including the bilateral putamen and extending to the left claustrum, as well as reduced FA values in the left posterior corona radiata. CONCLUSIONS: By combined analysis, alterations in subcortical GM areas and part of the corresponding association fiber area were detected. Compared with observations in homogeneous samples, our findings indicate that disruption of the limbic network may be intrinsic to BD.

Frontal white matter integrity predictors of adult alcohol treatment outcome.

BACKGROUND: Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment. METHODS: Forty-five treatment-seeking AUD inpatients and 30 healthy control subjects were included in the study. Six months after completing treatment, 16 of the AUD participants had resumed heavy use (RHU) and 29 others remained abstinent or drank minimally (treatment sustainers [TS]). Voxel-wise group comparisons (TS vs. RHU) were performed on fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity maps generated from each subject's diffusion tensor imaging scan at the start of treatment. RESULTS: We found significantly lower FA and significantly higher RD in the frontal lobes of the RHU group, relative to the TS group. The RHU group data are consistent with previous reports of abnormal frontal white matter tract abnormalities in persons with AUD. CONCLUSIONS: It is possible that the lower FA and higher RD in the RHU group reflect microstructural injury to frontal circuitries, and these may underlie the reduced cognitive control amid heightened reward sensitivity associated with resumption of heavy drinking.

ARVCF genetic influences on neurocognitive and neuroanatomical intermediate phenotypes in Chinese patients with schizophrenia.

OBJECTIVE: There are notable similarities between velocardiofacial syndrome and schizophrenia in terms of neurocognitive deficits and brain structural abnormalities. These similarities have supported the role of the armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) as a susceptibility gene in schizophrenia. This study investigated the relationships between haplotypes of the ARVCF gene and specific intermediate phenotypes in schizophrenia. We hypothesized that ARVCF gene haplotypes influence caudate nucleus volume, fractional anisotropy, and neurocognitive functioning in schizophrenia. METHOD: Between May 2006 and November 2009, 200 Chinese participants (125 patients with DSM-IV diagnosis of schizophrenia and 75 controls) were genotyped using blood samples, and a subset of 166 participants (99 patients with DSM-IV diagnosis of schizophrenia and 67 controls) underwent structural magnetic resonance imaging, diffusion tensor imaging, and completed neuropsychological testing. RESULTS: The haplotype T-G-A-T-T-G-G-C-T-G-T (ARVCF-Hap1) was significantly associated with fractional anisotropy of the caudate nucleus and executive functioning in patients. Specifically, patients with more copies of ARVCF-Hap1 have lower white matter integrity in caudate nucleus (P = .0008) and greater perseverative errors (P = .00003) on the Wisconsin Card Sorting Test. A trend of lower caudate volume (P = .015) in patients with more copies of ARVCF-Hap1 was also observed. CONCLUSIONS: These findings are consistent with known ARVCF gene effects on neurodevelopment in terms of cellular arrangement, migration, and intracellular signaling involving the striatum and may involve interactions with other brain networks such as prefrontal cortex, and they underscore the importance of imaging-genetic studies to elucidate the genetic influences underlying intermediate phenotypes in complex neurobehavioral disorders.

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder.

BACKGROUND: Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear. METHODS: We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI). RESULTS: We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls. LIMITATIONS: The major limitation of our study is the small number of patients with bipolar disorder. CONCLUSION: Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.