Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n = 7) or non-remitters (n = 6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤ 7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21) = 6.55, p = 0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final – baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r = 0.81, p = 0.002], with no significant association in healthy subjects [Fisher r-to-z p = 0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman = 0.62, p = 0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug.
Riluzole; generalized anxiety disorder; biomarkers; glutamate; N-Acetylaspartate; hippocampal volume; magnetic resonance spectroscopy
Functional neuroimaging studies have consistently shown abnormal limbic activation patterns in socially anxious individuals, but structural data on the amygdala and hippocampus of these patients are scarce. This study explored the existence of structural differences in the whole brain, amygdala, and hippocampus of subjects with clinical and subthreshold social anxiety compared to healthy controls. We hypothesized that there would be volumetric differences across groups, without predicting their direction (i.e. enlargement or reduction).
Subjects classified as having social anxiety disorder (n = 12), subthreshold social anxiety (n = 12) and healthy controls (n = 14) underwent structural magnetic resonance imaging scans. The amygdala and hippocampus were defined a priori as regions of interest and volumes were calculated by manual tracing. Whole brain volume was calculated using voxel-based morphometry.
The bilateral amygdala and left hippocampus were enlarged in socially anxious individuals relative to controls. The volume of the right hippocampus was enlarged in subthreshold social anxiety participants relative to controls. No differences were found across groups in respect to total brain volume.
Our results show amygdalar and hippocampal volume alterations in social anxiety, possibly associated with symptom severity. The time course of such alterations and the cellular and molecular bases of limbic plasticity in social anxiety should be further investigated.
Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT) to evaluate changes in the cerebral blood flow in tinnitus patients with normal hearing compared with healthy controls. Methods: Twenty tinnitus patients with normal hearing and 17 healthy controls, matched for sex, age and years of education, were subjected to Single Photon Emission Computed Tomography using the radiotracer ethylenedicysteine diethyl ester, labeled with Technetium 99 m (99 mTc-ECD SPECT). The severity of tinnitus was assessed using the “Tinnitus Handicap Inventory” (THI). The images were processed and analyzed using “Statistical Parametric Mapping” (SPM8). Results: A significant increase in cerebral perfusion in the left parahippocampal gyrus (pFWE <0.05) was observed in patients with tinnitus compared with healthy controls. The average total THI score was 50.8+18.24, classified as moderate tinnitus. Conclusion: It was possible to identify significant changes in the limbic system of the brain perfusion in tinnitus patients with normal hearing, suggesting that central mechanisms, not specific to the auditory pathway, are involved in the pathophysiology of symptoms, even in the absence of clinically diagnosed peripheral changes.
Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552), with the G-allele more frequent in patients than in controls. This polymorphism is likely functional, as predicted by PolyPhen and SIFT, but it was not associated with brain morphology in our study. In summary, we report a functional PRODH variant associated with schizophrenia that may have a neurochemical impact, altering brain function, but is not responsible for the cortical reductions found in the disorder.
Early life social adversity can influence stress response mechanisms and is associated with anxious behaviour and reductions in callosal area later in life.
To evaluate the association between perceptions of parental bonding in childhood/adolescence, hypothalamic-pituitary-adrenal (HPA) axis response, and callosal structural integrity in adult victims of severe urban violence with and without PTSD.
Seventy-one individuals with PTSD and 62 without the disorder were assessed with the Parental Bonding Instrument (PBI). The prednisolone suppression test was administered to assess cortisol levels, and magnetic resonance imaging was used to assess the total area of the corpus callosum (CC), as well as the areas of callosal subregions.
The PBI items related to the perception of ‘not having a controlling mother’ (OR 4.84; 95%CI [2.26–10.3]; p = 0.01), ‘having a caring father’ (OR 2.46; 95'%CI [1.18–5.12]; p = 0.02), and ‘not having controlling parents’ (OR 2.70; 95%CI [1.10–6.63]; p = 0.04) were associated with a lower risk of PTSD. The PTSD group showed a blunted response to the prednisolone suppression test, with lower salivary cortisol levels upon waking up (p = 0.03). Individuals with PTSD had smaller total CC area than those without the disorder, but these differences were not statistically significant (e-value = 0.34).
Healthy parental bonding, characterized by the perception of low parental control and high affection, were associated with a lower risk of PTSD in adulthood, suggesting that emotional enrichment and the encouragement of autonomy are protective against PTSD in adulthood.
To establish whether alterations of brain structures in Alzheimer's disease are associated with executive dysfunction.
Nineteen patients with Alzheimer's disease and 22 older control subjects underwent a comprehensive evaluation. The clock drawing test, digit span test, executive motor function test, Behavioral Assessment of the Dysexecutive Syndrome battery (Rule Shift Cards test), and Stroop test were used to evaluate executive dysfunction. A multiparametric approach using the FreeSurfer image analysis suite provided a description of volumetric and geometric features of the gray matter structures.
The cortical thickness maps showed a negative correlation between the Behavioral Assessment of the Dysexecutive Syndrome battery (Rule Shift Cards test) and the right middle frontal gyrus; a positive correlation between the executive motor function test and the left superior parietal gyrus, left middle temporal gyrus, bilateral supramarginal gyri, right middle frontal gyrus, and right precuneus; a negative correlation between the Stroop test (part III) and the right superior parietal gyrus; and a negative correlation between the Stroop test (part III) and the right middle temporal gyrus.
Executive dysfunction in Alzheimer's disease is correlated with alterations not only in the frontal areas but also within many temporal and parietal regions.
Executive Functions; Alzheimer's Disease; Magnetic Resonance Imaging
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
To investigate the mechanism underlying the anxiolytic properties of riluzole, a glutamate-modulating agent, we previously studied the effect of this drug on hippocampal N-Acetylaspartate (NAA) and volume in patients with Generalized Anxiety Disorder (GAD). In the same cohort, we now extend our investigation to the occipital cortex, a brain region that was recently implicated in the antidepressant effect of riluzole.
Fourteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. The healthy group did not receive riluzole treatment. Both groups underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) were used as the primary and secondary outcome measures, respectively.
At baseline, we found clusters of increased cortical thickness in the occipital region in GAD compared to healthy subjects. In the right hemisphere, eight weeks of treatment reduced occipital cortical thickness in the GAD group (t = 3.67, p = 0.004). In addition, the improvement in HAM-A scores was negatively correlated with post-treatment right occipital NAA (r = − 0.68, p = 0.008), and with changes in NAA levels (r = − 0.53, p = 0.051). In the left hemisphere, we found positive associations between changes in occipital cortical thickness and improvement in HAM-A (r = 0.60, p = 0.04) and PSWQ (r = 0.62, p = 0.03).
These pilot findings implicate the occipital cortex as a brain region associated with pathology and clinical improvement in GAD. In addition, the region specific effect of riluzole implies a distinct pathophysiology in the occipital cortex – compared to other, previously studied, frontolimbic brain structures.
Riluzole; generalized anxiety disorder; biomarkers; glutamate; N-Acetylaspartate; occipital cortex; magnetic resonance spectroscopy; structural MRI
Contrary to expectations derived from preclinical studies of the effects of stress, and imaging studies of adults with PTSD, there is no evidence of hippocampus atrophy in children with PTSD. Multiple pediatric studies have reported reductions in the corpus callosum – the primary white matter tract in the brain. Consequently, in the present study, Diffusion Tensor Imaging was used to assess corpus callosum white matter integrity in 17 maltreated children with PTSD and 15 demographically matched normal controls. Children with PTSD had reduced fractional anisotropy in the medial and posterior corpus, a region which contains interhemispheric projections from brain structures involved in circuits that mediate the processing of emotional stimuli and various memory functions --- core disturbances associated with a history of trauma. Further exploration of the effects of stress on corpus callosum and white matter development appears a promising strategy to better understanding the pathophysiology of PTSD in children.
Posttraumatic Stress Disorder; Imaging; DTI; children
To explore and validate the best returned latent class solution for reading and writing subtests from the Academic Performance Test (TDE).
A total of 1,945 children (6–14 years of age), who answered the TDE, the Development and Well-Being Assessment (DAWBA), and had an estimated intelligence quotient (IQ) higher than 70, came from public schools in São Paulo (35 schools) and Porto Alegre (22 schools) that participated in the ‘High Risk Cohort Study for Childhood Psychiatric Disorders’ project. They were on average 9.52 years old (standard deviation = 1.856), from the 1st to 9th grades, and 53.3% male. The mean estimated IQ was 102.70 (standard deviation = 16.44).
Via Item Response Theory (IRT), the highest discriminating items (‘a’>1.7) were selected from the TDE subtests of reading and writing. A latent class analysis was run based on these subtests. The statistically and empirically best latent class solutions were validated through concurrent (IQ and combined attention deficit hyperactivity disorder [ADHD] diagnoses) and discriminant (major depression diagnoses) measures.
A three-class solution was found to be the best model solution, revealing classes of children with good, not-so-good, or poor performance on TDE reading and writing tasks. The three-class solution has been shown to be correlated with estimated IQ and to ADHD diagnosis. No association was observed between the latent class and major depression.
The three-class solution showed both concurrent and discriminant validity. This work provides initial evidence of validity for an empirically derived categorical classification of reading, decoding, and writing performance using the TDE. A valid classification encourages further research investing correlates of reading and writing performance using the TDE.
Academic Performance Test; TDE; decoding; writing; validity
This study indirectly tested the hypothesis that individuals with autism spectrum disorders (ASDs) have impaired neural connections between the amygdala, fusiform face area, and superior temporal sulcus, key processing nodes of the “social brain.” This would be evidenced by abnormalities in the major fibre tracts known to connect these structures, including the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus.
Magnetic resonance diffusion tensor imaging was performed on 20 right-handed males (ASD = 10, controls = 10) with a mean age 13.5 ± 4.0 years. Subjects were group-matched according to age, full-scale IQ, handedness, and ethnicity. Fractional anisotropy was used to assess structural integrity of major fibre tracts. Voxel-wise comparison of white matter fractional anisotropy was conducted between groups using ANCOVA adjusting for age, full-scale IQ, and brain volume. Volumes of interest were identified using predetermined probability and cluster thresholds. Follow-up tractography was performed to confirm the anatomic location of all volumes of interest.
All volumes of interest were regions of lower FA and were observed primarily in pericallosal regions and temporal lobes. As confirmed by tractography, affected white matter structures included the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and corpus callosum/cingulum. Notably, some volumes of interest were adjacent to the fusiform face area, bilaterally, corresponding to involvement of the inferior longitudinal fasciculus. The largest effect sizes were noted for volumes of interest in the right anterior radiation of the corpus callosum/cingulum and right fusiform face area (inferior longitudinal fasciculus).
This study provides preliminary evidence of impaired neural connectivity in the corpus callosum/cingulum and temporal lobes involving the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus and superior longitudinal fasciculus in ASDs. These findings provide preliminary support for aberrant neural connectivity between the amygdala, fusiform face area, and superior temporal sulcus – temporal lobe structures critical for normal social perception and cognition.
autism; connectivity; diffusion tensor imaging; social brain; white matter
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
The role of structural brain changes and their correlations with neuropsychiatric symptoms and disability in Alzheimer's disease are still poorly understood.
To establish whether structural changes in grey matter volume in patients with mild Alzheimer's disease are associated with neuropsychiatric symptoms and disability.
Nineteen Alzheimer's disease patients (9 females; total mean age = 75.2 y old ±4.7; total mean education level = 8.5 y ±4.9) underwent a magnetic resonance imaging (MRI) examination and voxel-based morphometry analysis. T1-weighted images were spatially normalized and segmented. Grey matter images were smoothed and analyzed using a multiple regression design. The results were corrected for multiple comparisons. The Neuropsychiatric Inventory was used to evaluate the neuropsychiatric symptoms, and the Functional Activities Questionnaire and Disability Assessment for Dementia were used for functional evaluation.
A significant negative correlation was found between the bilateral middle frontal gyri, left inferior temporal gyrus, right orbitofrontal gyrus, and Neuropsychiatric Inventory scores. A negative correlation was found between bilateral middle temporal gyri, left hippocampus, bilateral fusiform gyri, and the Functional Activities Questionnaire. There was a positive correlation between the right amygdala, bilateral fusiform gyri, right anterior insula, left inferior and middle temporal gyri, right superior temporal gyrus, and Disability Assessment for Dementia scores.
The results suggest that the neuropsychiatric symptoms observed in Alzheimer's disease patients could be mainly due to frontal structural abnormalities, whereas disability could be associated with reductions in temporal structures.
Dementia; behavior disorder (Bpsd); Functional impairment; MRI
In this work, we present a method for the integration of feature and intensity information for non rigid registration. Our method is based on a free-form deformation model, and uses a normalized mutual information intensity similarity metric to match intensities and the robust point matching framework to estimate feature (point) correspondences. The intensity and feature components of the registration are posed in a single energy functional with associated weights. We compare our method to both point-based and intensity-based registrations. In particular, we evaluate registration accuracy as measured by point landmark distances and image intensity similarity on a set of seventeen normal subjects. These results suggest that the integration of intensity and point-based registration is highly effective in yielding more accurate registrations.
Life trauma is highly prevalent in the general population and posttraumatic stress disorder is among the most prevalent psychiatric consequences of trauma exposure. Brazil has a unique environment to conduct translational research about psychological trauma and posttraumatic stress disorder, since urban violence became a Brazilian phenomenon, being particularly related to the rapid population growth of its cities. This research involves three case-control studies: a neuropsychological, a structural neuroimaging and a molecular neuroimaging study, each focusing on different objectives but providing complementary information. First, it aims to examine cognitive functioning of PTSD subjects and its relationships with symptomatology. The second objective is to evaluate neurostructural integrity of orbitofrontal cortex and hippocampus in PTSD subjects. The third aim is to evaluate if patients with PTSD have decreased dopamine transporter density in the basal ganglia as compared to resilient controls subjects. This paper shows the research rationale and design for these three case-control studies.
Methods and design
Cases and controls will be identified through an epidemiologic survey conducted in the city of São Paulo. Subjects exposed to traumatic life experiences resulting in posttraumatic stress disorder (cases) will be compared to resilient victims of traumatic life experiences without PTSD (controls) aiming to identify biological variables that might protect or predispose to PTSD. In the neuropsychological case-control study, 100 patients with PTSD, will be compared with 100 victims of trauma without posttraumatic stress disorder, age- and sex-matched controls. Similarly, 50 cases and 50 controls will be enrolled for the structural study and 25 cases and 25 controls in the functional neuroimaging study. All individuals from the three studies will complete psychometrics and a structured clinical interview (the Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD Scale, Beck Anxiety Inventory, Beck Depression Inventory, Global Assessment of Function, The Social Adjustment Scale, Medical Outcomes Study 36-Item Short-Form Health Survey, Early Trauma Inventory, Clinical global Impressions, and Peritraumatic Dissociative Experiences Questionnaire). A broad neuropsychological battery will be administered for all participants of the neuropsychological study. Magnetic resonance scans will be performed to acquire structural neuroimaging data. Single photon emission computerized tomography with [(99m)Tc]-TRODAT-1 brain scans will be performed to evaluate dopamine transporters.
This study protocol will be informative for researchers and clinicians interested in considering, designing and/or conducting translational research in the field of trauma and posttraumatic stress disorder.