Walter Heindel

Limbic Scars: Long-Term Consequences of Childhood Maltreatment Revealed by Functional and Structural Magnetic Resonance Imaging

BACKGROUND Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. METHODS One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). RESULTS We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. CONCLUSIONS Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.

Osteoid Osteoma: CT-guided Percutaneous Radiofrequency Ablation and Follow-up in 47 Patients

PURPOSE To evaluate computed tomography (CT)-guided radiofrequency (RF) ablation as a minimally invasive therapy for osteoid osteoma with regard to technical and clinical success and immediate and delayed complications. MATERIALS AND METHODS Forty-seven patients (age range, 8-41 y; mean age, 19.6 y) with osteoid osteomas (femur, n = 25; tibia, n = 15; pelvis, n = 2; humerus, n = 1; ulna, n = 1; talus, n = 1; calcaneus, n = 1; vertebral body, n = 1) were treated with CT-guided RF ablation in 15 cases after one (n = 10) or two (n = 5) unsuccessful attempts at open surgical resection. Percutaneous therapy was performed with use of general or spinal anesthesia. After localization of the nidus with 1-3-mm CT sections, osseous access was established with either a 2-mm coaxial drill system or an 11-gauge Jamshidi needle. RF ablation was performed at 90 degrees C for a period of 4-5 minutes with use of a rigid RF electrode with a diameter of 1 mm. The procedures were regarded as technically successful if the tip of the RF electrode could be placed within the center of the nidus and could be heated to the desired temperature. Clinical success of treatment was defined as permanent relief of pain and return to normal function without additional treatment. In case of persistence or recurrence of symptoms after RF ablation, treatment was regarded as secondarily successful if permanent relief of symptoms could be achieved in a second procedure. RESULTS All procedures were technically successful. Clinical success was achieved in 94% of patients (44 of 47). Three patients had recurrence of pain 3, 5, and 7 months after treatment, respectively (mean observation interval, 22 mo). All recurrences were treated successfully in a second procedure (secondary success rate, 100%). No immediate or delayed complications were observed. CONCLUSION CT-guided percutaneous RF ablation is a simple, minimally invasive, safe and highly effective technique for treatment of osteoid osteoma.

Prospective Multicenter Cohort Study to Refine Management Recommendations for Women at Elevated Familial Risk of Breast Cancer: The EVA Trial

PURPOSE We investigated the respective contribution (in terms of cancer yield and stage at diagnosis) of clinical breast examination (CBE), mammography, ultrasound, and quality-assured breast magnetic resonance imaging (MRI), used alone or in different combination, for screening women at elevated risk for breast cancer. METHODS Prospective multicenter observational cohort study. Six hundred eighty-seven asymptomatic women at elevated familial risk (> or = 20% lifetime) underwent 1,679 annual screening rounds consisting of CBE, mammography, ultrasound, and MRI, read independently and in different combinations. In a subgroup of 371 women, additional half-yearly ultrasound and CBE was performed more than 869 screening rounds. Mean and median follow-up was 29.18 and 29.09 months. RESULTS Twenty-seven women were diagnosed with breast cancer: 11 ductal carcinoma in situ (41%) and 16 invasive cancers (59%). Three (11%) of 27 were node positive. All cancers were detected during annual screening; no interval cancer occurred; no cancer was identified during half-yearly ultrasound. The cancer yield of ultrasound (6.0 of 1,000) and mammography (5.4 of 1,000) was equivalent; it increased nonsignificantly (7.7 of 1,000) if both methods were combined. Cancer yield achieved by MRI alone (14.9 of 1,000) was significantly higher; it was not significantly improved by adding mammography (MRI plus mammography: 16.0 of 1,000) and did not change by adding ultrasound (MRI plus ultrasound: 14.9 of 1,000). Positive predictive value was 39% for mammography, 36% for ultrasound, and 48% for MRI. CONCLUSION In women at elevated familial risk, quality-assured MRI screening shifts the distribution of screen-detected breast cancers toward the preinvasive stage. In women undergoing quality-assured MRI annually, neither mammography, nor annual or half-yearly ultrasound or CBE will add to the cancer yield achieved by MRI alone.

Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy

AIMS To determine whether atrial fibrillation (AF) in stroke-free patients is associated with impaired cognition and structural abnormalities of the brain. AF contributes to stroke and secondary cognitive decline. In the absence of manifest stroke, AF can activate coagulation and cause cerebral microembolism which could damage the brain. METHODS AND RESULTS We cross-sectionally evaluated 122 stroke-free individuals with AF recruited locally within the German Competence Network on AF. As comparator, we recruited 563 individuals aged 37-84 years without AF from the same community. Subjects underwent 3 T magnetic resonance imaging to assess covert territorial brain infarction, white matter lesions, and brain volume measures. Subjects with evidence for stroke, dementia, or depression were excluded. Cognitive function was assessed by an extensive neuropsychological test battery covering the domains learning and memory, attention and executive functions, working memory, and visuospatial skills. Cognitive scores and radiographic measures were compared across individuals with and without AF by stepwise multiple regression models. Stroke-free individuals with AF performed significantly worse in tasks of learning and memory (ß = -0.115, P < 0.01) as well as attention and executive functions (ß = -0.105, P < 0.01) compared with subjects without AF. There was also a trend (P = 0.062) towards worse performance in learning and memory tasks in patients with chronic as compared with paroxysmal AF. Corresponding to the memory impairment, hippocampal volume was reduced in patients with AF. Other radiographic measures did not differ between groups. CONCLUSION Even in the absence of manifest stroke, AF is a risk factor for cognitive impairment and hippocampal atrophy. Therefore, cognition and measures of structural brain integrity should be considered in the evaluation of novel treatments for AF.

Reduced amygdala–prefrontal coupling in major depression: association with MAOA genotype and illness severity

The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

5-HTTLPR Biases Amygdala Activity in Response to Masked Facial Expressions in Major Depression

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. Increased amygdala reactivity has been discussed in the context of major depression. Recent studies reported that amygdala activity during conscious emotion processing is modulated by a functional polymorphism in the serotonin transporter gene (5-HTTLPR) in healthy subjects. In the present study, amygdala reactivity to displays of emotional faces was measured by means of fMRI at 3T in 35 patients with major depression and 32 healthy controls. Conscious awareness of the emotional stimuli was prevented via backward-masking to investigate automatic emotion processing. All subjects were genotyped for the 5-HTTLPR polymorphism. Risk allele carriers (S or LG) demonstrated increased amygdala reactivity to masked emotional faces, which in turn was significantly correlated with life-time psychiatric hospitalization as an index of chronicity. This might indicate that genetic variations of the serotonin transporter could increase the risk for depression chronification via altering limbic neural activity on a preattentive level of emotion processing.

Assessment of hemispheric language lateralization: a comparison between fMRI and fTCD.

The cerebral blood flow velocity (CBFV) in the basal arteries during a word-generation task was assessed by functional transcranial Doppler ultrasonography (fTCD) and by functional magnetic resonance imaging (fMRI). The study investigates how event-related CBFV modulations in the middle cerebral artery (MCA) relate to regional cerebral blood flow (rCBF) changes. Both fMRI and fTCD were used in 13 subjects (7 men, 6 women, aged 21 to 44 years). The maximum difference of relative CBFV changes between the left and right MCA during the word-generation task was used as the language laterality index (LIfTCD). For the fMRI examination during the nearly identical language task, the corresponding index was defined by LIfMRI = 100(NL − NR)/(NL + NR), where NL and NR refer to the numbers of voxels activated in the left and right hemisphere, respectively. The evoked CBFV changes expressed by LIfTCD and the corresponding laterality index, LIfMRI, estimated by fMRI showed a close linear relation (regression analysis: r = 0.95, p < 0.0001). The results of this study demonstrate that language-related velocity changes in the MCAs relate to rCBF increases in a linear fashion. Since the laterality indices assessed by fMRI and fTCD are in such close agreement both techniques can therefore be used in a complementary way.

Neurotrophic effects of electroconvulsive therapy: A proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression

Negatively balanced neurotrophic factors may be important in precipitating clinical depression. Recently, it has been reported that antidepressant therapy may exert positive neurotrophic effects. The aim of this study was to detect probable neurotrophic changes during electroconvulsive therapy (ECT). For this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons, and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho), and creatine (Cr) were measured in patients by localized proton magnetic resonance spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled, and the left amygdalar region was investigated by proton STEAM spectroscopy before and after unilateral ECT. The results were compared with 28 age- and gender-matched controls using nonparametric paired and unpaired tests. A significant increase in NAA was observed only in ECT responders (n=14; p=0.019). Five out of 14 nonresponders to ECT monotherapy were remeasured following a clinical improvement after continued ECT combined with antidepressants and were then found also to present a significant increase in NAA. In all successfully treated patients, parallel observations, that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged. In conclusion, our preliminary finding of increased NAA concentrations after successful ECT may indicate a probable neurotrophic effect of ECT.

Association of the functional −1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder

Serotonergic genes have been implicated in the pathogenesis of panic disorder and amygdala function in response to fearful stimuli. Regional brain activation on visual presentation of emotional facial stimuli was investigated in 20 patients with panic disorder by means of fMRI at 3 T. All patients were genotyped for the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms. In patients homozygous for the 5-HT1A -1019G risk allele (n=5), fearful stimuli were associated with a decreased activation of right prefrontal cortex regions. Patients homozygous for the 5-HT1A -1019G risk allele or patients carrying the short risk allele of the 5-HTTLPR (n=13) showed higher amygdala activation in response to happy faces. This exploratory study suggests a role of the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms on prefrontal cortex and amygdala activation patterns in response to emotional facial stimuli. These serotonergic polymorphisms might increase the risk for panic disorder by contributing to an altered processing of emotional stimuli.

Neuropeptide S receptor gene—converging evidence for a role in panic disorder

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn107Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case–control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.