The role of the prefrontal cortex as an executive oversight of posterior brain regions raises the question of the extent to which the anterior regions of the brain interconnect with the posterior regions. The aim of this study is to test the complexity of rostral white matter tracts, which connect anterior and posterior brain regions, in comparison to caudal white matter tracts and the corpus callosum. Diffusion tensor imaging (DTI) is a modality that measures fractional anisotropy (FA). Higher white matter complexity could result in a decrease of FA, possibly through denser intersection of fiber tracts. DTI was used to determine regional FA in 9 healthy bonnet macaques (Macaca radiata). Four regions of interest were included: anterior and posterior limbs of the internal capsule, the occipital lobe white matter, and the corpus callosum. FA of the anterior limbs of the internal capsule was lowest compared to all other regions of interest (Newman-Keuls (N-K); p < 0.0001), whereas FA of the corpus callosum was highest (N-K; p < 0.0001). The posterior limbs of the internal capsule and the occipital white matter were not distinguishable but exhibited intermediate FA in comparison to the former (N-K; p < 0.0001) and the latter (N-K; p < 0.0001). The current study demonstrates that FA, a measure of white matter complexity, can vary markedly as a function of region of interest. Moreover, validation of these findings using neurohistological studies and replication in human samples appears warranted.
Diffusion tensor imaging; fractional anisotropy; white matter; gap junctions; nonhuman primates; neuroimaging; neurodevelopment
The study examined the relation between paternal age at the time of birth and risk of schizophrenia in the adult offspring.
Data from the birth cohort of the Prenatal Determinants of Schizophrenia study were used in this study. Virtually all members of this birth cohort had prospective information about paternal age at the time of the offspring's birth. Subjects with schizophrenia and other schizophrenia spectrum disorders (N=71) among members of this birth cohort were previously ascertained. In separate analyses, paternal age was modeled as a continuous variable and as a categorical variable, and its relation with the risk of adult schizophrenia and other schizophrenia spectrum disorders and with the risk of schizophrenia separately were examined.
There was a marginally significant, monotonic association between advancing paternal age and risk of adult schizophrenia and schizophrenia spectrum disorders. The association held after the analysis controlled for the effects of maternal age and other potential con-founders. Similar results were observed when only subjects with schizophrenia were included in the analysis.
Advanced paternal age at the time of birth of the offspring may be a risk factor for adult schizophrenia.
The Panic Disorder Severity Scale (PDSS) is promising to be a standard global rating scale for panic disorder. In order for a clinical scale to be useful, we need a guideline for interpreting its scores and their changes, and for defining clinical change points such as response and remission.
We used individual patient data from two large randomized controlled trials of panic disorder (total n=568). Study participants were administered the PDSS and the Clinical Global Impression (CGI)-Severity and -Improvement. We applied equipercentile linking technique to draw correspondences between PDSS and CGI-Severity, numeric changes in PDSS and CGI-Improvement, and percent changes in PDSS and CGI-Improvement.
The interpretation of the PDSS total score differed according to the presence or absence of agoraphobia. When the patients were not agoraphobic, score ranges 0–1 corresponded with “Normal,” 2–5 with “Borderline”, 6–9 with “Slightly ill”, 10–13 with “Moderately ill”, and 14 and above with “Markedly ill.” When the patients were agoraphobic, score ranges 3–7 meant “Borderline ill,” 8–10 “Slightly ill,” 11–15 “Moderately ill,” and 16 and above “Markedly ill.” The relationship between PDSS change and CGI-Improvement was more linear when measured as percentile change than as numeric changes, and was indistinguishable for those with or without agoraphobia. The decrease by 75–100% was considered “Very much improved,” that by 40–74% “Much improved,” and that by 10–39% “Minimally improved.”
We propose that “remission” of panic disorder be defined by PDSS scores of 5 or less and its “response” by 40% or greater reduction.
Panic disorder; Psychiatric Status Rating Scale; Panic Disorder Severity Scale; Clinical Global Impression Scale; Equipercentile linking
Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls.
Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators.
Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator.
Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity.
Corticotropin releasing factor; hippocampus; stress; metabolic syndrome; food insecurity; obesity
Administration of doxapram hydrochloride, a respiratory stimulant, is experienced by panic disorder patients to be similar to panic attacks but has reduced emotional effect in normal volunteers thus providing a laboratory model of panic for functional imaging. Six panic patients and seven normal control subjects underwent positron emission tomography with 18F-deoxyglucose imaging after a single-blinded administration of either doxapram or a placebo saline solution. Saline and doxapram were administered on separate days in counterbalanced order. Patients showed a greater heart rate increase on doxapram from saline than controls, indicating differential response. On the saline placebo day, patients had greater prefrontal relative activity than controls. In response to doxapram, patients tended to decrease prefrontal activity more than controls, and increased cingulate gyrus and amygdala activity more than controls. This suggests that panic disorder patients activate frontal inhibitory centers less than controls which may lower the threshold for panic.
doxapram; PET; panic; prefrontal cortex; amygdala; neuroimaging
Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.
Nonhuman primates; corticotropin-releasing hormone; early-life stress; serotonin transporter gene; major depression; anxiety disorders; gene by environment interaction
We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA) – an amino acid considered reflective of neuronal density/functional integrity – using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N = 10) or control rearing conditions (N = 9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted.
Early-Life Stress; Nonhuman Primate; Magnetic Resonance Spectroscopy; Hippocampus; N-Acetyl-Aspartate; Brain laterality
We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging (1H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ’s and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.
intelligence; anxiety; white matter; choline; magnetic resonance spectroscopic imaging
Schizophrenia is etiologically heterogeneous. It is anticipated, but unproven, that subgroups will differ in neuropathology and that neuroimaging may reveal these differences. The optimal imaging condition may be at rest, where greater variability is observed than during cognitive tasks, which more consistently reveal hypofrontality. We previously demonstrated symptom and physiologic differences between familial and sporadic schizophrenia patients and hypothesized that the groups would show different resting regional cerebral blood flow (rCBF) patterns.
Ten familial and sixteen sporadic schizophrenia patients and nine comparison subjects had single photon emission computed tomography imaging during passive visual fixation. Images were spatially normalized into Talairach coordinates and analyzed for group rCBF differences using SPM with a Z value threshold of 2.80, p < .001.
The subgroups had similar age, gender, illness duration, and medication treatment. Sporadic patients had hypofrontality (anterior cingulate, paracingulate cortices, left dorsolateral and inferior–orbitofrontal), whereas familial patients had left temporoparietal hypoperfusion; all of these regions show resting activity in healthy subjects. Both groups hyperperfused the cerebellum/pons and parahippocampal gyrus; additional hyperperfusion for sporadic patients was observed in the fusiform; familial patients also hyperperfused the hippocampus, dentate, uncus, amygdala, thalamus, and putamen.
Familial and sporadic schizophrenia patients had different resting rCBF profiles, supporting the hypothesis that certain subgroups have distinct neural underpinnings. Different neuropathologic processes among subgroups of schizophrenia patients may account for the prior contradictory results of resting imaging studies.
Default state; familial; hypofrontality; resting; schizophrenia; self-representation; SPECT
Deficit syndrome (DS) schizophrenia patients have smooth pursuit eye movement (SPEM) dysfunction. We examined if they also had smell identification deficits, since social affiliation is related to olfaction in other mammals.
Sixty-seven patients had DS assessments: 31 patients had SPEM and 50 had Smell Identification Test (SIT) assessments, and 14 patients had both measurements.
DS patients had worse SPEM and SIT performance than the non-DS patients. Areas under the receiver–operator characteristic (ROC) curves for SIT and SPEM were both fairly accurate in identifying the DS. The odds ratio (OR) for the DS for impaired versus normal SPEM was 6.21 (95% confidence interval [CI]: 1.21, 32.25) and for microsmia versus normosmia was 10.4 (95% CI: 1.23, 88.18). Further analyses showed that the association of SIT with both SPEM and the DS could account for the SPEM-DS association.
We found a strong association between the DS and SIT scores suggesting that the neural substrates of olfaction may be related to social affiliation in humans, as they are in other mammals. These data further support the notion that the DS defines a homogeneous subgroup of schizophrenia patients and further suggest that dysfunction in the neural circuitry of olfaction may contribute to its pathophysiology.
Schizophrenia; negative symptoms; social function; deficit syndrome; odor identification; eye tracking
Research evaluating the relationship of comorbidity to treatment outcome for panic disorder has produced mixed results. The current study examined the relationship of comorbid depression and anxiety to treatment outcome in a large-scale, multi-site clinical trial for cognitive-behavior therapy (CBT) for panic disorder. Comorbidity was associated with more severe panic disorder symptoms, although comorbid diagnoses were not associated with treatment response. Comorbid generalized anxiety disorder (GAD) and major depressive disorder (MDD) were not associated with differential improvement on a measure of panic disorder severity, although only rates of comorbid GAD were significantly lower at posttreatment. Treatment responders showed greater reductions on measures of anxiety and depressive symptoms. These data suggest that comorbid anxiety and depression are not an impediment to treatment response, and successful treatment of panic disorder is associated with reductions of comorbid anxiety and depressive symptoms. Implications for treatment specificity and conceptual understandings of comorbidity are discussed.
Panic disorder; Comorbidity; Treatment outcome; Anxiety; Depression
Coinfection with HIV hastens the progression of liver disease in persons with hepatitis C virus (HCV) infection. As mortality directly due to HIV continues to decrease among persons who are HIV-positive, coinfection with HCV has emerged as a leading cause of death. There is increasing attention to the need to actively treat HCV infection in HIV/HCV coinfected patients. Current HCV treatment with pegylated interferon and ribavirin achieves sustained viral response in up to 40% of coinfected patients but has numerous neuropsychiatric side effects. Providers are hesitant to begin HCV treatment in the coinfected population given the high prevalence of existing psychiatric illness, cognitive impairment, and substance use disorders. There is an urgent need for research into the psychiatric and behavioral predictors of HCV treatment adherence and virologic outcome, as well as into the optimal psychiatric management of the neuropsychiatric sequelae of HCV therapy.
Cognitive–behavioral therapy (CBT) and pharmacotherapy are similarly effective for treating panic disorder with mild or no agoraphobia, but little is known about the mechanism through which these treatments work. The present study examined some of the criteria for cognitive mediation of treatment change in CBT alone, imipramine alone, CBT plus imipramine, and CBT plus placebo. Ninety-one individuals who received 1 of these interventions were assessed before and after acute treatment, and after a 6-month maintenance period. Multilevel moderated mediation analyses provided preliminary support for the notion that changes in panic-related cognitions mediate changes in panic severity only in treatments that include CBT.
mediation; cognitive–behavioral therapy; pharmacotherapy; imipramine; panic disorder
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
Evidence suggests that white matter integrity may play an underlying pathophysiological role in schizophrenia. N-acetylaspartate (NAA), as measured by Magnetic Resonance Spectroscopy (MRS), is a neuronal marker and is decreased in white matter lesions and regions of axonal loss. It has also been found to be reduced in the prefrontal and temporal regions in patients with schizophrenia. Diffusion Tensor Imaging (DTI) allows one to measure the orientations of axonal tracts as well as the coherence of axonal bundles. DTI is thus sensitive to demyelination and other structural abnormalities. DTI has also shown abnormalities in these regions.
MRS and DTI were obtained on 42 healthy subjects and 40 subjects with schizophrenia. The data was analyzed using regions of interests in the Dorso-Lateral Prefrontal white matter, Medial Temporal white matter and Occipital white matter using both imaging modalities.
NAA was significantly reduced in the patient population in the Medial Temporal regions. DTI anisotropy indices were also reduced in the same Medial Temporal regions. NAA and DTI-anisotropy indices were also correlated in the left medial temporal region.
Our results implicate defects in the medial temporal white matter in patients with schizophrenia. Moreover, MRS and DTI are complementary modalities for the study of white matter disruptions in patients with schizophrenia.