Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging.

The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal's adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

The effects of sexual abuse on female adolescent brain structures.

Objective: Sexual abuse (SA) is known for its effects on brain structures in adolescents. We aimed to explore if SA has any effect on limbic and prefrontal cortex (PFC) structures. We hypothesized that children with SA would have a thinner PFC with larger amygdala and hippocampus that lead to aberrations in threat detection, orientation and response circuit; that would be highly adaptive in a dangerous environment in the short term. Method: We included 57 SA and 33 healthy control (HC) female participants. In addition to psychiatric evaluation, we acquired 3 T MR images from all participants. We compared prefrontal cortical thicknesses, hippocampus and amygdala volumes between groups. Results: The age and education levels of study groups were matched, however, IQ scores and socioeconomic status (SES) scores of the SA group were lower than the controls. Total CTQ scores of the SA group were higher than the HC. Nevertheless, the mean value of sexual abuse scores was above the cut-off scores only for the SA participants. SA participants had larger right and left hippocampus and right amygdala volumes than the controls. SA group had reduced inferior frontal gyrus cortical thickness (T=3.5, p<0.01, cluster size=694 mm2, x=51 y=-30 z=6) than HC group. None of the structural findings were correlated with total or sexual abuse CTQ scores. Conclusion: Children with SA history has structural abnormalities in threat detection, orientation and response circuit. SA victims with no psychiatric diagnosis have a high probability of psychiatric problems with a possible contribution of these aberrations. SA cases that do not have a diagnosis must not be overlooked as they may have structural changes in emotion related brain regions. Careful follow-up is needed for all of all SA cases.

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.

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice.

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP ND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination.

From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural MRI, may be increased dendritic spine density, alterations in astrocyte volume, and adaptations within intracortical myelin. Myelin plasticity is crucial for neurological function, and active myelination is required for learning and memory. However, the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown. We used a motor skill learning paradigm in male mice to evaluate experience-dependent brain plasticity by voxel-based morphometry (VBM) in longitudinal MRI, combined with a cross-sectional immunohistochemical investigation. Whole-brain VBM revealed nonlinear decreases in gray matter volume (GMV) juxtaposed to nonlinear increases in white matter volume (WMV) within GM that were best modeled by an asymptotic time course. Using an atlas-based cortical mask, we found nonlinear changes with learning in primary and secondary motor areas and in somatosensory cortex. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed an increase in myelin immunoreactivity followed by a return towards baseline levels. Further investigations using quantitative confocal microscopy confirmed these changes specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity. Together, these observations indicate a nonlinear increase of intracortical myelin during learning and support the hypothesis that myelin is a component of structural changes observed by VBM during learning.

Brain areas associated with resilience to depression in high-risk young women.

Previous structural brain-imaging studies in first-degree relatives of depressed patients showed alterations that are generally accepted as vulnerability markers for depression. However, only half of the relatives had depression at follow-up, while the other half did not. The aim of this study was to identify the brain areas associated with resilience to depression in high-risk subjects with familial depression. We recruited 59 young women with a history of depressed mothers. Twenty-nine of them (high-risk group [HRG]) had no depression history, while 30 (depressive group) had at least 1 depressive episode in adolescence. The brain structures of the groups were compared through voxel-based morphometry and analysis of cortical thickness. Individual amygdala nuclei and hippocampal subfield volumes were measured. The analysis showed larger amygdala volume, thicker subcallosal cortex and bilateral insula in the women in the HRG compared with those in the depressive group. In addition, we detected more gray matter in the left temporal pole in the HRG. The larger gray matter volume and increased cortical thickness in the key hub regions of the salience network (amygdala and insula) and structurally connected regions in the limbic network (subcallosal area and temporal pole) might prevent women in the HRG from converting to depression.

A longitudinal study of lateral ventricle volumes in deficit and non-deficit schizophrenia.

Although it is generally accepted that negative symptoms of schizophrenia are associated with larger lateral ventricles, this general assumption could not be validated in patients with primary negative symptoms. To elucidate this issue, we conducted a five-year longitudinal study, including deficit (n = 13) and non-deficit (n = 26) schizophrenia patients with healthy controls (n = 18). Analysis with linear mixed effects modeling showed that both the left and the right lateral ventricles of the deficit patients enlarged more than the non-deficit patients. Our results suggest that structural alterations in deficit patients might follow a different trajectory than those in non-deficit patients.

[Small frontal gray matter volume in first-episode depression patients]. / Ilk Atak Depresyon Hastalarinda Azalmis Frontal Korteks Hacimleri.

OBJECTIVE: Brain imaging studies have shown that depressed individuals suffer from inadequate frontal lobe functions vis à vis smaller frontal lobes. The effects of depression's recurrent nature and long-term antidepressant treatment are not definitely known. This study aimed to examine frontal lobe volume at the onset of clinical depression by including first-episode drug-naive depressed patients. METHOD: The study included 23 first-episode drug-free major depression patients diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and 28 healthy age- and sex-matched controls. Cranial magnetic resonance (MR) images were obtained in both groups using a 1.5 Tesla device. Gray and white matter volumes in the frontal lobes were measured using the Medical Image Processing Analysis and Visualization (MIPAV) computer program. RESULTS: Frontal gray matter volume in the patients was lower than that in the control group. White matter and total intracranial volume did not differ between the 2 groups. Small gray matter volume was not correlated with the duration or severity of illness. CONCLUSION: The results of this study indicate that frontal lobe gray matter volume is low in first-episode depressed patients and is independent of both illness severity and duration. This result suggests that the observed changes in the frontal lobe could have occurred before the clinical symptoms of depression were observed.

Testing an Internet-Based Turkish Obesity Behavioral Therapy Program: A Randomized Study. / Internet Tabanli Türkçe Obezite Davranisçi Terapi Programinin Test Edilmesi: Bir Seçkisiz Çalisma.

OBJECTIVE: Behavioral treatment is recommended as the first line intervention for the prevention of health problems pertaining to obesity. Internet-based programs are used to provide cognitive behavioral therapy for psychiatric disorders and systemic diseases to a large number of patients at low cost. The aim of this study is to develop the first internet based Turkish obesity behavioral therapy program and test its short-term effectiveness. METHOD: A Turkish web-based behavioral therapy program based on the behavioral strategies employed in the Diabetes Prevention Program was generated. In order to test the effectiveness of this internet-based program an eight week randomized study was conducted. A total of 101 overweight participants with body mass index in the 25-40 range were randomly assigned to an eight-week weight loss program using either the Internet Behavior Therapy (IBT, n=51) or e-mail education (EE, n=50). The participants in the IBT group were provided access to an Internet program that provided videos teaching behavioral weight-loss skills as well as a self-monitoring platform to calculate the daily calorie balance. The participants in the EE group received weekly e-mails with information on healthy eating, physical exercises and weight loss for eight weeks. The primary outcome measure was the observed weight change at the end of the 8 weeks. RESULTS: In the analyses wherein baseline weight was carried forward for missing data, the IBT produced significantly larger mean weight loss in comparison to the EE at the end of the 8 weeks [2.28 kg (2.11) vs. 0.74 kg (1.57), p=0.001]. The participants in the IBT group, when compared to the EE group, were also more likely to achieve a clinically significant weight loss of 5% of their initial body weight at the end of the 8-week study period (17.6% vs. 2%, p=0.016). CONCLUSION: The participants who received a structured IBT intervention lost significantly more weight after two months, compared to those who received weekly informational emails regarding weight loss. Internet-based behavioral therapy programs may have the potential to serve as a low-cost alternative for obese patients.

Cortical thickness and VBM in young women at risk for familial depression and their depressed mothers with positive family history.

It has been demonstrated that compared to low-risk subjects, high-risk subjects for depression have structural and functional alterations in their brain scans even before the disease onset. However, it is not known if these alterations are related to vulnerability to depression or epiphenomena. One way to resolve this ambiguity is to detect the structural alterations in the high-risk subjects and determine if the same alterations are present in the probands. In this study, we recruited 24 women with the diagnosis of Major Depressive Disorder (MDD) with recurrent episodes and their healthy daughters (the high-risk for familial depression group; HRFD). We compared structural brain scans of the patients and HRFG group with those of 24 age-matched healthy mothers and their healthy daughters at similar ages to the HRFD group; respectively. Both cortical gray matter (GM) volume and thickness analyses revealed that HRFD daughters and their MDD mothers had similar GM differences in two regions: the right temporoparietal region and the dorsomedial prefrontal cortex. These results suggested that the observed alterations may be related to trait clinical and neurophysiological characteristics of MDD and may present before the onset of illness.

Investigating Connectivity of Orbitomedial Prefrontal Region in a Patient with Traumatic Brain Injury. / Bir Travmatik Beyin Hasari Olgusunda Orbitomedial Prefrontal Bölge Baglantilarinin Incelenmesi.

The majority of the research studying the prefrontal region has focused on gray matter injury. However, recent studies show that damage to white matter also contributes to the development of cognitive impairment after traumatic brain injury (TBI). Through the use of diffusion tensor imaging (DTI), it is now possible to assess the white matter fiber pathways between brain regions. With Diffusion Tensor Tractography (DTT), fibers of interest can be three dimensionally reconstructed and associated measurements can be performed. In this paper, we present the case of an individual that suffered from panic attacks, behavioral changes, auditory hallucinations and disturbing bodily sensations after traumatic brain injury. The patient was evaluated with a detailed clinical and neuropsychological assessment, magnetic resonance imaging (MRI) and DTI. MRI revealed cystic encephalomalasia with a diameter of 3.4 cm in the left orbitomedial frontal region. With DTT, major white matter tracts of the traumatized area were compared with symmetrical tracts in the contralateral side. Streamline count for the right inferior fronto-occipital fasciculus (iFOF) was 54 while no streamlines could be found for the left iFOF. For the left uncinate fasciculus and the left cingulum, streamline counts were significantly lower compared with the right side (62% and 34% lower; respectively). White matter damage in TBI can cause dysfunction of different brain regions through disruption of connections with the traumatized area. In this case report, we emphasized that symptoms were not limited with dysfunction of the traumatized region and the regular functions of other brain regions were also affected via the disturbance of connection pathways.

The relationship between the anterior corpus callosum size and prefrontal cortex volume in drug-free depressed patients.

INTRODUCTION: An evolving literature suggests a volume reduction and a loss of functional integrity of prefrontal cortex in depressed patients. Interhemispheric prefrontal functional integrity is mediated via the anterior portion of the corpus callosum. Until recently interhemispheric fibers connecting prefrontal cortex have not been well defined. In this study, we compared the corpus callosum area of depressed patients with controls using a novel schema proposed by Hofer and Frahm (2006) which defined a specific anterior callosal area for prefrontal interhemispheric fibers. We further investigated the correlation between callosal area and prefrontal cortical volume. METHODS: Thirty-six patients with major depressive disorder and thirty-three healthy controls were recruited. All subjects were psychotropic medication-free and right-handed. The imaging was performed on a 1.5T MR unit (Magnetom Vision Siemens). The images obtained from 3D MP-RAGE sequence were used for analyses. Medical Image Processing, Analyzing and Visualization (MIPAV) software was used for callosal and prefrontal measurements. RESULTS: Depressed patients had reduced prefrontal cortical volume and a loss of the normal callosal/gray matter correlation, but normal white matter volume and normal callosal areas. LIMITATIONS: It is not known if the observed changes were preexisting or acquired. CONCLUSION: Our results indicate that the normal structural relationship between anterior callosal area and prefrontal cortical volume is disrupted in major depressive disorder and that the disruption is due to reduced cortical volume rather than to changes in interhemispheric connections.