Distinct Basal Brain Functional Activity and Connectivity in the Emotional-Arousal Network and Thalamus in Patients With Functional Constipation Associated With Anxiety and/or Depressive Disorders.

OBJECTIVE: Functional constipation (FC) is a common gastrointestinal disorder. Anxiety and/or depressive disorders are common in patients with FC (FCAD). Brain dysfunction may play a role in FC, but the contribution of comorbid anxiety and/or depression in patients with FC is poorly understood. METHODS: Sixty-five FC patients and 42 healthy controls (HCs) were recruited, and a hierarchical clustering algorithm was used to classify FC patients into FCAD and patients without anxiety/depressive status (FCNAD) based on neuropsychological assessment. Resting-state functional magnetic resonance imaging measures including fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity were used to investigate brain functional differences. RESULTS: Thirty-seven patients were classified as FCAD, and 28 patients were classified as FCNAD; as compared with HC, both groups showed decreased activity (fALFF) in the perigenual anterior cingulate cortex (pACC), dorsomedial prefrontal cortex (DMPFC), and precuneus; enhanced precentral gyrus-thalamus connectivity and attenuated precuneus-thalamus connectivity in FCAD/FCNAD highlighted the thalamus as a critical connectivity node in the brain network (pFWE < .05). In comparison with FCNAD/HC, the FCAD group also had decreased fALFF in the orbitofrontal cortex (OFC) and thalamus, and increased OFC-hippocampus connectivity. In the FCNAD group, brain activities (pACC/DMPFC) and connection (precuneus-thalamus) had correlations only with symptoms; in the FCAD group, brain activities (OFC, pACC/DMPFC) and connectivities (OFC-hippocampus/precentral gyrus-thalamus) showed correlations with both constipation symptoms and anxiety/depressive status ratings. Mediation analysis indicated that the relationship between abdominal distension and OFC activity was completely mediated by anxiety in FCAD. CONCLUSIONS: These findings provide evidence of differences in brain activity and functional connectivity between FCAD and FCNAD, potentially providing important clues for improving treatment strategies.

[The effect of multichannel electrostimulation of neck nervous structures on the brain connectivity of patients with depressive disorders]. / Vliianie mnogokanal'noi élektrostimuliatsii nervnykh struktur shei na konnektivnost' golovnogo mozga u patsientov s depressivnym rasstroistvom.

AIM: To study neurophysiological processes during multichannel electrostimulation in patients with depressive disorder. MATERIAL AND METHODS: The study involved 6 patients with depressive disorder (F33). The technology noninvasive multichannel stimulation of neck neural struct SYMPATHOKOR-01 device. Clinical and psychometric methods, functional neuroimaging (fMRTP) and multichannel electroencephalography (EEG) were used to assess treatment effect. RESULTS: In all patients, fMRTP and EEG results show the disturbances of brain connectivity, which are correlated with the clinical state of the disease, before treatment. After five stimulation procedures, there is an increase in functional connection of the medial prefrontal cortex (according to rs-fMRI results) and an increase in the synchronization of various parts of the cortex (EEG results). CONCLUSION: The results demonstrate the possibilities of multichannel electrical stimulation of the neck nervous structures to restore the intracerebral connections disturbed during depression due to the activation of neuroplasticity.

Common and specific dimensions of internalizing disorders are characterized by unique patterns of brain activity on a task of emotional cognitive control.

Alterations in neural systems underlying cognitive control are well-documented across individuals with various internalizing disorders. The current study examined how individual differences in underlying traits related to internalizing disorders influence brain activation, as assessed by fMRI, when cognitive control must be exerted to make a decision about the emotional valence (positive, negative) of a task-relevant word displayed concurrently with a task-irrelevant emotional face. Taking a bi-factor model approach, fifty-five middle-aged female participants were characterized on symptom level on a common internalizing latent factor representing shared symptoms across anxiety and depression, as well as on specific factors remaining after taking the common internalizing factor into account: low positive affect, anxious arousal, and anxious apprehension. Contrasting activation on trials requiring higher vs. lower control revealed that higher levels of the Common Internalizing factor are associated with less deactivation of regions of the default mode network. Higher levels of the Low Positive Affect-specific factor are associated with less differentiation in engagement of portions of the fronto-parietal control network, while higher levels of the Anxious Arousal-specific factor are associated with less of a differentiation in activation of the thalamus. No effects were observed for level of the Anxious Apprehension-specific factor. These results suggest that prior findings of alterations in default mode activity associated with depression may not be specific to depressive symptoms per se but may characterize internalizing symptoms more generally. In addition, they suggest that reduced engagement of cognitive control regions may be more associated with low positive affect than depressive symptoms more generally.

The neural correlates of mindfulness-induced depression reduction in adults with autism spectrum disorder: A pilot study.

Adults with autism spectrum disorder (ASD) experience high rates of depression and anxiety, and some evidence suggests mindfulness-based stress reduction (MBSR) is effective in reducing these symptoms. However, the neural mechanisms of symptom alleviation, and benefit of MBSR beyond education/support groups are unknown. Maladaptive forms of self-reflection are linked to ASD, depression, and anxiety. In this pilot study, we hypothesized (a) MBSR would reduce depression and anxiety in adults with ASD and (b) a mechanism of symptom alleviation would be increased blood oxygen level-dependent signal in neural self-reflection hubs. Twenty-eight adults were randomly assigned to an 8-week MBSR group (n = 15) or a support group (n = 13) that met for the same amount of time with relaxation education materials. Based on previous self-reflection literature in ASD, regions of interest (ROIs) were middle cingulate cortex (MCC) and ventromedial prefrontal cortex (vmPFC). Only the MBSR group demonstrated significant reductions in depression, and neither group significantly changed in anxiety. Only the MBSR group increased activity of right MCC during self-reflection, and the increase correlated with depression alleviation. There were no changes in vmPFC for the MBSR group or either ROI for the support/education group. Seed-to-voxel connectivity analysis revealed that only the MBSR group increased functional connectivity between right MCC and pre/postcentral gyrus, suggesting MBSR may increase primary sensorimotor input to higher order cognitive brain regions. Taken together, MBSR may be effective for reducing depression in adults with ASD, and the neural mechanism may be increasing frontal circuit involvement during self-directed thought.

Targeting the affective brain-a randomized controlled trial of real-time fMRI neurofeedback in patients with depression.

Functional magnetic resonance imaging neurofeedback (fMRI-NF) training of areas involved in emotion processing can reduce depressive symptoms by over 40% on the Hamilton Depression Rating Scale (HDRS). However, it remains unclear if this efficacy is specific to feedback from emotion-regulating regions. We tested in a single-blind, randomized, controlled trial if upregulation of emotion areas (NFE) yields superior efficacy compared to upregulation of a control region activated by visual scenes (NFS). Forty-three moderately to severely depressed medicated patients were randomly assigned to five sessions augmentation treatment of either NFE or NFS training. At primary outcome (week 12) no significant group mean HDRS difference was found (B = -0.415 [95% CI -4.847 to 4.016], p = 0.848) for the 32 completers (16 per group). However, across groups depressive symptoms decreased by 43%, and 38% of patients remitted. These improvements lasted until follow-up (week 18). Both groups upregulated target regions to a similar extent. Further, clinical improvement was correlated with an increase in self-efficacy scores. However, the interpretation of clinical improvements remains limited due to lack of a sham-control group. We thus surveyed effects reported for accepted augmentation therapies in depression. Data indicated that our findings exceed expected regression to the mean and placebo effects that have been reported for drug trials and other sham-controlled high-technology interventions. Taken together, we suggest that the experience of successful self-regulation during fMRI-NF training may be therapeutic. We conclude that if fMRI-NF is effective for depression, self-regulation training of higher visual areas may provide an effective alternative.

Single session real-time fMRI neurofeedback has a lasting impact on cognitive behavioral therapy strategies.

To benefit from cognitive behavioral therapy (CBT), individuals must not only learn new skills but also strategically implement them outside of session. Here, we tested a novel technique for personalizing CBT skills and facilitating their generalization to daily life. We hypothesized that showing participants the impact of specific CBT strategies on their own brain function using real-time functional magnetic imaging (rt-fMRI) neurofeedback would increase their metacognitive awareness, help them identify effective strategies, and motivate real-world use. In a within-subjects design, participants who had completed a clinical trial of a standardized course of CBT created a personal repertoire of negative autobiographical stimuli and mood regulation strategies. From each participant's repertoire, a set of experimental and control strategies were identified; only experimental strategies were practiced in the scanner. During the rt-fMRI neurofeedback session, participants used negative stimuli and strategies from their repertoire to manipulate activation in the anterior cingulate cortex, a region implicated in emotional distress. The primary outcome measures were changes in participant ratings of strategy difficulty, efficacy, and frequency of use. As predicted, ratings for unscanned control strategies were stable across observations, whereas ratings for experimental strategies changed after neurofeedback. At follow-up one month after the session, efficacy and frequency ratings for scanned strategies were predicted by neurofeedback during the rt-fMRI session. These results suggest that rt-fMRI neurofeedback created a salient and durable learning experience for patients, extending beyond the scan session to guide and motivate CBT skill use weeks later. This metacognitive approach to neurofeedback offers a promising model for increasing clinical benefits from cognitive behavioral therapy by personalizing skills and facilitating generalization.

Reduced resting-state thalamostriatal functional connectivity is associated with excessive daytime sleepiness in persons with and without depressive disorders.

BACKGROUND: Excessive daytime sleepiness (EDS) is a common and significant problem encountered in affective illness, however, the biological underpinnings of EDS in persons with psychiatric disorders are not clear. This study evaluated the associations between thalamic connectivity with cortical and subcortical brain regions with EDS in persons with and without depressive disorders (DD). METHODS: Resting-state functional connectivity magnetic resonance imaging scans from 67 unmedicated young to middle-aged women with current DD (n = 30), remitted DD (n = 13), and healthy controls (n = 24) were utilized to examine the associations between thalamic connectivity with cortical/subcortical structures and EDS. RESULTS: After correction for multiple comparisons and adjustment for age, habitual sleep duration, and depressive symptomatology, reduced resting-state connectivity between the bilateral thalamus and left rostral striatum (caudate/putamen) was significantly associated with EDS. LIMITATIONS: Causal inferences between thalamostriatal connectivity and EDS could not be determined. CONCLUSIONS: These results further implicate the role of the striatum and thalamus as central components of the experience of EDS. Further research is indicated to clarify the specific role these structures play in EDS in psychiatric disorders.

Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.

Vascular pathology is common in late-life depression, contributing to changes in cerebral function. We examined whether late-life depression was associated with differences in cerebral blood flow (CBF) and whether such differences were related to vascular risk and cerebrovascular pathology, specifically white matter hyperintensity (WMH) volumes. Twenty-three depressed elders and 20 age- and sex-matched elders with no psychiatric history completed cranial 3T MRI. MRI procedures included a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition obtained while on room air and during a hypercapnia challenge allowing for calculation of cerebrovascular reactivity (CVR). Brain segmentation identified frontal, temporal, parietal and cingulate sub-regions in which CBF and CVR were calculated. The depressed group exhibited an anterior-posterior gradient in CBF, with lower CBF throughout the frontal lobe but higher CBF in the parietal lobe, temporal lobe, thalamus and hippocampus. A similar anterior to posterior gradient was observed in the cingulate cortex, with anterior regions exhibiting lower CBF and posterior regions exhibiting higher CBF. We did not observe any group differences in CVR measures. We did not observe significant relationships between CBF and CVR with vascular risk or WMH volumes, aside from an isolated finding associating higher WMH volumes with lower CBF in the rostral anterior cingulate cortex. Decreased anterior CBF in depressed elders might reflect decreased metabolic activity in these regions, while increased posterior CBF may represent either compensatory processes or different activity of posterior intrinsic functional networks. Future work should examine how these findings are related to compensatory changes with aging.

An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents.

Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents. Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs). Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

5-(4-hydroxy-3-dimethoxybenzylidene)-rhodanine (RD-1)-improved mitochondrial function prevents anxiety- and depressive-like states induced by chronic corticosterone injections in mice.

Most current pharmacologic antidepressant treatments target monoaminergic systems confronts some problems such as low rate of remission and high risk for relapse indicating new therapeutic strategy is urgently need. Evidences showed that impairments in mitochondrial function were associated with the pathogenesis of mood disorders and improvement in its function may be a novel therapeutic choice. In the present study, effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4-thiazolidinone (RD-1) were investigated in mice model of depression/anxiety induced by corticosterone (20 mg/kg) subcutaneously repeated injections in 5-week male BALB/c mice. Our results showed that five weeks of corticosterone administration induced anxiety/depressive-like behavioral changes, including decreased central activities in open field test, increased the immobility time in forced swimming test and the latency in the novelty-suppressed feeding test, as well as reduced bodyweight. Results showed that oral administration with RD-1 at the doses of 25, 50, and 100 mg/kg for five weeks significantly improved the anxiety/depressive-like behavioral changes induced by corticosterone. In glucose metabolism analysis by photon emission computed tomography/-computed tomography (PET/CT) imaging, corticosterone significantly deactivated the prefrontal cortex (PFC), temporal lobe and hippocampus. RD-1 treatment obviously improved the energy metabolism in the involved brain regions. In primary cultured hippocampal neuron, corticosterone reduced speed of anterograde transport, yet speed of retrograde transport was increased. Furthermore, RD-1 enhanced the mitochondrial anterograde transport to supply energy for the neurotransmitter release. In conclusion, RD-1 prevents anxiety/depressive-like behavior of mice induced by corticosterone repeated injections with novel mechanism of improvement in the mitochondrial function.

Depressive symptoms and regional cerebral blood flow in Alzheimer's disease.

Depressive symptoms are common in patients with Alzheimer's disease (AD) and increase the caregiver burden, although the etiology and pathologic mechanism of depressive symptoms in AD patients remain unclear. In this study, we tried to clarify the cerebral blood flow (CBF) correlates of depressive symptoms in AD, excluding the effect of apathy and anxiety. Seventy-nine consecutive patients with AD were recruited from outpatient units of the Memory Clinic of Okayama University Hospital. The level of depressive symptoms was evaluated using the depression domain of the Neuropsychiatric Inventory (NPI). The patients underwent brain SPECT with 99mTc-ethylcysteinate dimer. After removing the effects of age, anxiety and apathy scores of NPI, and five subscales of Addenbrooke's Cognitive Examination-revised (ACE-R), correlation analysis of NPI depression scores showed a significant cluster of voxels in the left middle frontal gyrus (Brodmann area 9), similar to the areas in the simple correlation analysis. The dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD, and the area on the left side especially may be closely related to the depressive symptoms revealed by NPI.

Mitochondrial function is related to alterations at brain SPECT in depressed patients.

INTRODUCTION: 99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO) retention in brain is proportional to cerebral blood flow and related to both the local hemodynamic state and to the cellular content of reduced glutathione. Alterations of the regional distribution of 99mTc-HMPAO retention, with discrepant results, have been reported at functional brain imaging of unipolar depression. Since mitochondrial involvement has been reported in depressed patients, the aim of the study was to explore whether the 99mTc-HMPAO retention at single-photon emission computed tomography in depressed patients may relate to different levels of mitochondrial function. METHODS: All patients had audiological and muscular symptoms, somatic symptoms that are common in depression. Citrate synthase (CS) activity assessed in muscle mitochondria correlated strongly with the activities of three mitochondrial respiratory chain enzymes and was used as a marker of mitochondrial function. K-means clustering performed on CS grouped eight patients with low and 11 patients with normal CS. Voxel-based analysis was performed on the two groups by statistical parametric mapping. RESULTS: Voxel-based analysis showed significantly higher 99mTc-HMPAO retention in the patients with low CS compared with the patients with normal CS in the posterior and inferior frontal cortex, the superior and posterior temporal cortex, the somato-sensory cortex, and the associative parietal cortex. CONCLUSION: Low muscle CS in depressed patients is related to higher regional 99mTc-HMPAO retention that may reflect cerebrovascular adaptation to impaired intracellular metabolism and/or intracellular enzymatic changes, as previously reported in mitochondrial disorder. Mitochondrial dysfunction in varying proportions of the subjects may explain some of the discrepant results for 99mTc-HMPAO retention in depression.

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study.

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings.

OBJECTIVE: The authors previously identified depression-specific differences in brain responses to an emotional challenge in patients with bipolar and unipolar mood disorder. In this study, potential markers of bipolar risk and resilience were examined in a new cohort of lithium-responsive bipolar patients and their healthy siblings. METHOD: Changes in regional cerebral blood flow (rCBF) were measured with [(15)O]water positron emission tomography after induction of transient sadness in nine euthymic lithium responders and nine healthy siblings. The patterns of change in these groups were compared, and then they were contrasted with previous findings on bipolar responders to valproate. RESULTS: Common to all three groups with induced sadness were rCBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings. DISCUSSION: Common changes with emotional challenge were identified in bipolar patients and their healthy siblings. These were not seen previously in healthy subjects without a family history of mood disorder, suggesting a potential marker of bipolar risk. The siblings' unique increases in the medial frontal cortex appear to identify a compensatory response in this at-risk group, as this pattern was not seen previously in healthy subjects without depression risk factors. This differential change pattern in patients and their siblings highlights the role of the anterior cingulate and medial frontal regions in mediating resiliency and vulnerability in bipolar disorder families.

[Effect of scalp acupuncture on glucose metabolism in brain of patients with depression].

OBJECTIVE: To observe the effect of scalp acupuncture (SA) on the glucose metabolism in different regions of brain in patients with depression by positron emission computed tomography (PET). METHODS: Twelve depressive patients were treated by scalp acupuncture on middle line of vertex (MS5), middle line of forehead (MS1) and bilateral lateral line 1 of forehead (MS2), once a day for six days per week, and received PET detection on different region of brain before and after 6 weeks acupuncture treatment. Semiquantitative analysis was used to compare the average values of radioactive count gotten from various brain regions before and after treatment, which could reflect the condition of glucose metabolism at the brain region detected. RESULTS: SA could increase the glucose metabolism at bilateral frontal lobes, bilateral parietal lobes, right occipital lobe, right caudate nucleus, right cingulated gyrus and left cerebellum and decrease that at right temporal lobe and bilateral thalamus. CONCLUSION: SA on MS5, MS1 and MS2 in depressive patients could influence the glucose metabolism in various brain regions. It primarily illustrated that the mechanism of SA in treating depression is related with its regulation on cortex-limbic circuitry dysfunction and increase the glucose metabolism in various brain regions.

Ventromedial prefrontal cortex and amygdala dysfunction during an anger induction positron emission tomography study in patients with major depressive disorder with anger attacks.

CONTEXT: Although a variety of functional neuroimaging studies have used emotion induction paradigms to investigate the neural basis of anger in control subjects, no functional neuroimaging studies using anger induction have been conducted in patient populations. OBJECTIVE: To study the neural basis of anger in unmedicated patients with major depressive disorder with anger attacks (MDD + A), unmedicated patients with MDD without anger attacks (MDD - A), and controls. DESIGN: We used positron emission tomography, psychophysiologic measures, and autobiographical narrative scripts in the context of an anger induction paradigm. SETTING: Academic medical center. PARTICIPANTS: Thirty individuals, evenly divided among the 3 study groups. INTERVENTIONS: In separate conditions, participants were exposed to anger and neutral autobiographical scripts during the positron emission tomography study. Subjective self-report and psychophysiologic data were also collected. MAIN OUTCOME MEASURES: Voxelwise methods were used for analyses of regional cerebral blood flow changes for the anger vs neutral contrast within and between groups. RESULTS: Controls showed significantly (P<.001) greater regional cerebral blood flow increases in the left ventromedial prefrontal cortex during anger induction than patients with MDD + A, whereas these differences were not present in other between-group analyses. Also, in controls, an inverse relationship was demonstrated between regional cerebral blood flow changes during anger induction in the left ventromedial prefrontal cortex and left amygdala, whereas in patients with MDD + A there was a positive correlation between these brain regions during anger induction. There was no significant relationship between these brain regions during anger induction in patients with MDD - A. CONCLUSION: These results suggest a pathophysiology of MDD + A that is distinct from that of MDD - A and that may be responsible for the unique clinical presentation of patients with MDD + A.

Correlation between cerebral blood flow and items of the Hamilton Rating Scale for Depression in antidepressant-naive patients.

BACKGROUND: The purpose of this study was to correlate the basal cerebral blood flow (CBF) in patients with major depressive disorder (MDD) with the score for each of the 21 questions in the Hamilton Rating Scale for Depression (HRSD), in order to determine the cerebral regions associated with each item. METHODS: Fourteen antidepressant-naive patients with unipolar depression (DSM-IV criteria for MDD) participated in this study with a HRSD score of >/=20 points. CBF images obtained by SPECT were analyzed by SPM99 software. The significant correlation threshold for a priori regions (frontocortical and limbic regions) was a Z value of at least 2.25 and clusters formed by more than 10 voxels. RESULTS: Items 1, 6, 11 and 20 were positively correlated with right medial frontal gyrus; item 7 was negatively correlated with bilateral medial frontal gyrus. Items 2 and 10 were positively correlated with right anterior and medial cingulate, respectively. Item 5 was negatively correlated with the left amygdala. Item 9 was negatively correlated with bilateral insula, and item 16 with right insula. Items 12 and 14 were positively correlated with right and left precentral frontal gyrus, respectively. LIMITATIONS: The small sample size and only out-patients included in the study. CONCLUSIONS: The frontal cortex plays an important role in the expression of MDD symptoms. Not all the symptoms evaluated correlated with one single structure, which may explain the diverse results reported in the literature. These preliminary results support the necessity of further analyses by symptoms that could provide more specific information on the pathophysiology of MDD.

Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings.

BACKGROUND: In functional brain imaging studies of major depressive disorder (MDD), regional abnormalities have been most commonly found in prefrontal cortex, anterior cingulate gyrus, and temporal lobe. We examined baseline regional metabolic abnormalities and metabolic changes from pretreatment to posttreatment in subjects with MDD. We also performed a preliminary comparison of regional changes with 2 distinct forms of treatment (paroxetine and interpersonal psychotherapy). METHODS: Twenty-four subjects with unipolar MDD and 16 normal control subjects underwent resting F 18 ((18)F) fluorodeoxyglucose positron emission tomography scanning before and after 12 weeks. Between scans, subjects with MDD were treated with either paroxetine or interpersonal psychotherapy (based on patient preference), while controls underwent no treatment. RESULTS: At baseline, subjects with MDD had higher normalized metabolism than controls in the prefrontal cortex (and caudate and thalamus), and lower metabolism in the temporal lobe. With treatment, subjects with MDD had metabolic changes in the direction of normalization in these regions. After treatment, paroxetine-treated subjects had a greater mean decrease in Hamilton Depression Rating Scale score (61.4%) than did subjects treated with interpersonal psychotherapy (38.0%), but both subgroups showed decreases in normalized prefrontal cortex (paroxetine-treated bilaterally and interpersonal psychotherapy-treated on the right) and left anterior cingulate gyrus metabolism, and increases in normalized left temporal lobe metabolism. CONCLUSIONS: Subjects with MDD had regional brain metabolic abnormalities at baseline that tended to normalize with treatment. Regional metabolic changes appeared similar with the 2 forms of treatment. These results should be interpreted with caution because of study limitations (small sample size, lack of random assignment to treatment groups, and differential treatment response between treatment subgroups).

Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents.

Cumulative data suggest depression in adulthood being connected to reduced availability of brain serotonin while the role of dopamine remains less specific. Prospective studies have shown a continuity of depressive episodes from childhood to adulthood, combined with poor social function and excess mortality. The object of this study was to examine whether alterations in brain serotonin and/or dopamine transporter levels are already present in depressive children and adolescents. We examined 41 drug-naive patients (aged 7-17) by single photon emission tomography (SPET) using iodine-123-labelled 23-carbomethoxy-3P3(iodophenyl) tropane [123I]beta-CIT as a tracer for monoamine transporters. In addition to the ordinary clinical examination, the patients were given a structured interview and information was gathered from teachers and parents with questionnaires. The diagnoses were established by consensus evaluation between three child psychiatrists. To test the serotonin hypothesis and the dopamine hypothesis regarding depression in children and adolescents, the series was divided into groups with depression present (31) and no depression present (10). In this study, the depressive child and adolescent patients had significantly higher serotonin transporter availability (P < 0.02) in the hypothalamic/midbrain area. Age did not correlate to the hypothalamic/midbrain serotonin transporter binding ratio. No significant difference in dopamine transporter availability in striatum was found between the depressive and the nondepressive children and adolescents.

Clinical and biological findings in a case with 48-hour bipolar ultrarapid cycling before and during valproate treatment.

BACKGROUND: The rare cases of patients with 48-hour ultrarapid cycling allow close investigation of mood cycles in affective disorders, because rhythmic changes in psychopathologic state and biological parameters happen very precisely. METHOD: A 67-year-old white man who had experienced bipolar 48-hour ultrarapid cycling (DSM-IV 296.80) for several years was studied without any medication and then again studied 4 weeks later during treatment with valproate (1800 mg/day). RESULTS: Objective and self ratings revealed pronounced manic states 1 day and depressed states the following day, which were found to be accompanied by rhythmic fluctuations in behavior and electroencephalographic parameters, blood cortisol and growth hormone levels (both elevated on depressive days), and urinary metanephrine (dopamine metabolite) and norepinephrine levels (both elevated on manic days). Using single photon emission computed tomography, regional blood flow in the left thalamus was lower than in the right thalamus on the manic day, while symmetric perfusion of the thalamus was found on the depressive day. Under valproate treatment, the patient remitted completely, and significant rhythmic changes in most of the biological parameters were no longer detectable. CONCLUSION: The biological findings in this patient with bipolar 48-hour ultrarapid cycling, which correspond to those in other types of affective disorders, suggest that disturbances in the diencephalon-pituitary axis may be especially correlated to pathologic changes of mood.