The social phobia psychotherapy research network. The first multicenter randomized controlled trial of psychotherapy for social phobia: rationale, methods and patient characteristics.

This paper presents the Social Phobia Psychotherapy Research Network. The research program encompasses a coordinated group of studies adopting a standard protocol and an agreed-on set of standardized measures for the assessment and treatment of social phobia (SP). In the central project (study A), a multicenter randomized controlled trial, refined models of manualized cognitive-behavioral therapy and manualized short-term psychodynamic psychotherapy are compared in the treatment of SP. A sample of 512 outpatients will be randomized to either cognitive-behavioral therapy, short-term psychodynamic psychotherapy or waiting list. Assessments will be made at baseline, at the end of treatment and 6 and 12 months after the end of treatment. For quality assurance and treatment integrity, a specific project using highly elaborated measures has been established (project Q). Study A is complemented by 4 interrelated add-on projects focusing on attachment style (study B1), on cost-effectiveness (study B2), on variation in the serotonin transporter gene in SP (study C1) and on structural and functional deviations of the hippocampus and amygdala (study C2). Thus, the Social Phobia Psychotherapy Research Network program enables a highly interdisciplinary research into SP. The unique sample size achieved by the multicenter approach allows for studies of subgroups (e.g. comorbid disorders, isolated vs. generalized SP), of responders and nonresponders of each treatment approach, for generalization of results and for a sufficient power to detect differences between treatments. Psychological and biological parameters will be related to treatment outcome, and variables for differential treatment indication will be gained. Thus, the results provided by the network may have an important impact on the treatment of SP and on the development of treatment guidelines for SP.

Amygdala and hippocampal volumes and cognition in adult survivors of childhood abuse with dissociative disorders.

OBJECTIVE: Trauma-exposed individuals with post-traumatic stress disorder (PTSD) display reduced amygdala and hippocampal size and impaired cognition. However, studies on trauma-exposed individuals with dissociative amnesia (DA) or dissociative identity disorder (DID) are lacking. METHOD: Twenty-three young women who had experienced severe childhood sexual/physical abuse, diagnosed with DA/DID or PTSD, and 25 healthy control subjects were subjected to 3D structural magnetic resonance imaging of amygdala and hippocampus and a clinical and neuropsychological investigation. RESULTS: Compared with controls, trauma-exposed subjects with PTSD (n = 10) displayed significantly reduced amygdala and hippocampal size and significantly impaired cognition. By contrast, trauma-exposed subjects with DA or DID (n = 13) displayed normal amygdala and hippocampal size and normal cognition. CONCLUSION: We report for the first time volumetric results in subjects with DA/DID without PTSD as comorbid diagnosis. Our results indicate preserved amygdala and hippocampal size and preserved cognition in subjects with these disorders.

Enlarged amygdala volume and reduced hippocampal volume in young women with major depression.

BACKGROUND: Evidence is increasing that amygdala and hippocampus show significant structural abnormalities in affective disorders. Two previous studies found enlarged amygdala size in subjects with recent-onset major depression. METHOD: Amygdala and hippocampal volumes were assessed in 17 young women with major depressive disorder and 17 healthy matched control subjects by use of three-dimensional structural magnetic resonance imaging. The severity of depressive symptoms was assessed using the Hamilton Depression Scale and the Beck Depression Inventory. RESULTS: Compared with control subjects, depressive subjects had significantly larger (+13 %) amygdala volumes and significantly smaller (-12%) hippocampal volumes. Amygdala and hippocampal volumes were not significantly correlated with disorder-related variables. CONCLUSIONS: Our results are consistent with previous findings of structural abnormalities of amygdala and hippocampus in subjects with recent-onset major depression. It may be suggested that the size of the amygdala is enlarged in the first years of the disorder, and may decrease with prolonged disorder duration.

Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study.

BACKGROUND: In cell culture experiments, flupirtine maleate (FLU), a triaminopyridine compound, was able to protect neuronal cells from apoptotic cell death induced by prion protein fragments and beta-amyloid peptides. As FLU is a clinically safe drug, the authors started a double-blind placebo-controlled study in patients with Creutzfeldt-Jakob disease (CJD). METHODS: Twenty-eight patients with CJD were randomized to an oral treatment with either FLU (n = 13) or matching placebo (PLA; n = 15). For inclusion and continuing the study, the patients had to achieve at least 50% in two of the subscales of the dementia tests employed. A battery of standardized questionnaires was employed to monitor the progression of the disease. The main outcome variable was the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog); the difference between baseline and the best score under treatment was defined as the primary efficacy variable for hypothesis testing. RESULTS: CJD types were homogeneously distributed among the treatment groups. Patients treated with FLU showed significantly less deterioration in the dementia tests than patients treated with PLA. The mean change in ADAS-Cog (baseline to best) was +8.4 (+/-15.3) in the FLU group and +20.6 (+/-15.1) in the PLA group (p = 0.02, one-sided t-test). CONCLUSIONS: FLU has beneficial effects on cognitive function in patients with CJD. These positive results also may suggest a treatment potential of FLU in other neurodegenerative disorders. However, further studies are necessary.

Impaired and enhanced attentional function in children with attention deficit/hyperactivity disorder.

BACKGROUND: The symptom domain of inattention in attention deficit/hyperactivity disorder (ADHD) suggests that there are neuropsychological fields of attention in which subjects with ADHD express deficits. However, studies using differentiated neuropsychological attentional tests in ADHD are lacking. METHOD: A consecutive series of 35 subjects with ADHD aged 9-12 years were assessed on a computer-driven neuropsychological test battery for attentional functions. Their performance was classified according to the data of a normative sample of 187 healthy subjects aged 9-12 years, and compared with the performance of 35 matched healthy control subjects. RESULTS: According to normative data, most ADHD subjects performed on all attentional measures within the normal range. Comparisons with the control group revealed that ADHD subjects reacted faster on all attentional tests, yielding statistical significance for the Go/No go test and the Divided Attention test. They also performed with significantly fewer errors on the Divided Attention test. On the Go/No go test, Visual Scanning test and Attentional Shift test ADHD subjects committed significantly more errors than control subjects. CONCLUSIONS: Our results suggest a differential pattern rather than a deficit pattern of attentional functions in ADHD. It is suggested that the more rapid response style of ADHD subjects leads to a more erroneous performance in self-paced attentional tasks and to a better performance in externally paced attentional tasks. However, neuropsychological tests of attention do not contribute to the clinical diagnosis of ADHD.

Implicit and explicit memory after focal thalamic lesions.

BACKGROUND: Lesions of the thalamus interfere with cognitive functions mainly in the area of declarative learning and memory. Little is known about the role the thalamus plays in implicit learning. OBJECTIVE: To study explicit and implicit learning and memory in subjects with thalamic lesions and to analyze the influence of lesion characteristics on cognitive performance. METHODS: The authors studied the performance of 15 subjects with focal thalamic infarction or hemorrhage on a comprehensive neuropsychological test battery focusing on tests of explicit memory and learning of a nondeclarative motor skill. Subjects with thalamic lesions were compared to 15 healthy matched control subjects and to a clinical control group of 22 subjects who had sustained basal ganglia lesions. RESULTS: Subjects with thalamic lesions showed well-preserved intellectual and executive functions but demonstrated deficits on measures of attention and psychomotor speed, explicit memory, and implicit visuomotor sequence learning. Lesion size in the thalamus was clearly related to subjects' long-term explicit memory performance. However, few of the neuropsychological deficits found seemed specific to the long-term neuropsychological outcome of focal thalamic infarctions. Subjects with lesions in the basal ganglia demonstrated similar deficits. CONCLUSIONS: Focal subcortical lesions in the thalamus and the basal ganglia lead to a similar profile of neuropsychological deficits. Lesions in the thalamus not only affect declarative memory but also interfere with nondeclarative motor skill learning.

Emotional priming of facial affect identification in schizophrenia.

Twenty-three schizophrenia subjects were compared with healthy and clinical control subjects on an emotional priming task. Positive and negative emotional facial expressions were presented as primes, followed by a neutral pattern mask, then an emotionally neutral face as target. The prime-mask-target sequence was arranged to allow conscious perception of only the targets. Subjects had to judge if they had seen a pleasant or an unpleasant facial expression. All subjects judged the neutral target as significantly more unpleasant when negative emotional facial expressions were presented as primes as compared with positive or neutral facial expressions as primes. This judgment shift was significantly stronger in schizophrenia subjects than in control subjects. The stronger priming of schizophrenia subjects may reflect a stronger influence of automatically processed emotional stimuli on judgments. We suggest that increased spreading activation of emotional information might be related to low social/emotional functioning of the individual with schizophrenia.

Amygdala lesion in temporal lobe epilepsy subjects impairs associative learning of emotional facial expressions.

To investigate the role of unilateral amygdala lesions on processing emotions, 22 drug-resistant temporal lobe epilepsy (TLE) subjects (12 with left-sided and ten with right-sided focus) were tested, after anterior temporal lobectomy or selective amygdalo-hippocampectomy on two associative learning tasks containing emotional and neutral facial expressions, respectively. Volumetric lesion analysis was performed on the basis of 3-D MR images. No effects of lesion side were found in TLE subjects. Taken the extent of amygdala damage into account, an interaction effect could be shown between task (learning of neutral facial expressions versus emotional facial expressions) and group (subjects with little versus considerable amygdala damage), indicating worse performance of subjects with considerable amygdala damage in learning emotional facial expressions. Subjects with considerable amygdala damage were also significantly impaired in learning emotional facial expressions when compared with control subjects.

[Psychopathologic symptoms and cognitive test performance in schizophrenic patients]. / Psychopathologische Symptomatik und kognitive Leistungen schizophrener Patienten.

Psychopathological symptoms and cognitive test performance were examined in 34 acute schizophrenic patients. The results of a clusteranalytic approach in order to distinguish groups of patients with different syndromes were disappointing. Three dimensions of negative, hallucinatory-delusional, and disorganised symptoms could be established by factor analysis. The disorganised symptom dimension showed strong and significant relations to mnestic and intellectual impairments of the patients. Hallucinatory-delusional symptoms were related to deficits in tests of visual memory and visual search. Negative symptoms were not related to cognitive impairments of the patients. The results are discussed in respect of other studies reporting correlations of schizophrenic symptoms and cognitive disturbances, and with regard to hypotheses of brain dysfunction in schizophrenia. In future research, consideration of the three main dimensions of schizophrenic symptoms could be useful to reduce the heterogeneity of schizophrenic samples.

Obsessive-compulsive disorder and ventromedial frontal lesions: clinical and neuropsychological findings.

OBJECTIVE: The authors sought to determine the long-term outcome of subjects with severe and refractory obsessive-compulsive disorder (OCD) who had undergone ventromedial frontal leukotomy during the 1970s. Special emphasis was given to the analysis of specific lesion sites. METHOD: Sixteen OCD subjects who had undergone ventromedial frontal leukotomy were evaluated clinically and neuropsychologically and compared to seven well comparison OCD subjects without leukotomy. The 16 leukotomized subjects were divided into three groups according to the main lesion sites as determined by current magnetic resonance imaging scans. RESULTS: The leukotomized OCD subjects showed significant improvement of obsessive-compulsive symptoms; subjects with frontostriatal lesions tended to have improved most. The subjects with combined diagnoses of OCD and obsessive personality disorder (N = 3) had improved significantly less. Of 11 subjects with lesions of the ventral striatum, eight had developed substance dependence postoperatively. Intellectual functions were largely preserved in subjects with ventromedial frontal lesions only or frontostriatal lesions. However, all subjects showed subnormal performance on the Wisconsin Card Sorting Test. Subjects with lesions of the dorsolateral frontal convexity also showed memory problems, attentional slowing, and lower performance IQ. CONCLUSIONS: Restricted ventromedial frontal leukotomy should be discussed as a last-resort treatment for severe and refractory OCD but not obsessive personality disorder. Lesions of the ventral striatum were significantly related to the occurrence of substance dependence, suggesting a role of this area in human addictive behavior.

The decoding of emotional concepts in patients with focal cerebral lesions.

The effects of focal brain lesions on the decoding of emotional concepts in facial expressions were investigated. Facial emotions are hierarchically organized patterns comprising (1) structural surface features, (2) discrete (primary) emotional categories and (3) secondary dimensions, such as valence and arousal. Categorical decoding was measured using (1) selection of category labels and selection of the named emotion category; (2) matching one facial expression with two choice expressions. Dimensional decoding was assessed by matching one face with two different expressions with regard to valence or arousal. 70 patients with well documented cerebral lesions and 15 matched hospital controls participated in the study. 27 had left brain damage (LBD; 10 frontal, 10 temporal, 7 parietal); 37 had right brain damage (RBD; 15 frontal, 11 temporal, 11 parietal). Six additional patients had lesions involving both frontal lobes. Right temporal and parietal lesioned patients were markedly impaired in the decoding of primary emotions. The same patients also showed a reduced arousal decoding. In contrast to several patients with frontal and left hemisphere lesions, emotional conceptualization and face discrimination was not independent in these groups. No group differences were observed in valence decoding. However, right frontal lesions appeared to interfere with the discrimination of negative valence. Moreover, a distraction by structural features was noted in RBD when facial identities were varied across stimulus and response pictures in matching tasks with differing conceptual load. Our results suggest that focal brain lesions differentially affect the comprehension of emotional meaning in faces depending on the level of conceptual load and interference of structural surface features.

Categorical and dimensional decoding of emotional intonations in patients with focal brain lesions.

The present study attempts to elucidate whether cerebral brain lesions differentially affect the crossmodal decoding of emotional intonations in semantically meaningless sentences. Forty patients with well-documented lesions and 12 matched hospital controls participated in the study. Twenty-one had left brain damage (LBD: 12 with anterorolandic (anterior) and 9 with retrorolandic-infrasylvian (posterior) lesions); 19 had right brain damage (RBD: 12 anterior, 7 posterior lesions). The decoding of emotion categories was measured using (a) multiple choice of verbal labels and (b) matching one emotional vocalization (joy, fear, sadness, or anger) with two choice facial expressions. Crossmodal dimensional decoding was assessed by matching vocalizations with two facial expressions with regard to emotional valence or arousal. Results indicate that labeling was reduced in all lesion groups as compared to that in controls. Crossmodal categorical recognition was impaired in RBD, whereas LBD performance was comparable to controls. However, in the dimensional decoding task, a reduced recognition of valence in LBD and arousal in RBD was observed. An analysis of localizational subgroups revealed that subjects with left ventral frontal lesions, which in part extended into the adjacent right hemisphere, were predominantly impaired in the crossmodal identification of valence, whereas right temporoparietal lesions affected arousal decoding. Our results suggest that lateralized lesions may differentially affect the crossmodal recognition of dimensional concepts such as valence and arousal.

Bilateral paramedian thalamic infarction with persisting signs of frontal lobe dysfunction.

Cognition and behavior of a 46-year-old woman with a bilateral paramedian thalamic infarction is discussed with regard to dysfunctions of executive behaviors associated with frontal lobe function. The patient displayed marked disturbances in traditional neuropsychological tests measuring frontal lobe functions, as well as in attentional and mnemonic tasks depending on strategic behavior or on response flexibility, response shifting, or response inhibition. Behaviorally, the patient showed considerable apathy, confusion and perseverative tendencies in the acute state, and a diminished psychic self-activation in the chronic state. In spite of long-lasting rehabilitation efforts, the patients' neurobehavioral deficits remained and became obvious in situations with high cognitive demands.

Mood changes after surgery for tumors of the cerebral cortex.

OBJECTIVE: To identify cortical lesion sites associated with particular mood states. DESIGN: A prospective study of patients with tumors affecting the cerebral cortex. The patients were examined neuropsychologically 1 to 5 days preoperatively and 2 to 10 days, several months, and several years postoperatively. Only data from the preoperative and the first postoperative examination were considered in this report. SETTING: Neurosurgical department of the University of Heidelberg (Germany). PATIENTS AND SUBJECTS: A consecutive sample of 141 patients with brain tumors (84 female and 57 male) with cortical lesions caused by microsurgical tumor resection; 29 clinical control patients (having undergone surgery for slipped disks); and 18 normal control subjects. MAIN OUTCOME MEASURE: Preoperative and postoperative mood state as measured with an adjective checklist. RESULTS: (1) Patients with lesions of the ventral frontal cortex or lesions of the temporoparietal cortex reported postoperatively significantly (P < .01) worse mood states (anxiety/depression, irritability/anger, fatigue) than did patients in the other lesion and control groups. (2) A more detailed lesion analysis revealed that lesions of heteromodal frontal or parietal association cortexes, combined with paralimbic lesions, were responsible for the negative mood states. Lesions of the sensorimotor cortexes ameliorated the negative effects of heteromodal and paralimbic lesions. (3) Lesion laterality did not influence the mood states. CONCLUSIONS: Heteromodal cortexes may be especially concerned with emotionally relevant operations. A loss of these functions deprives limbic structures of one of their main sources of input and is therefore likely also to produce changes in feelings, that is, emotional states.

Memory disturbances following anterior communicating artery rupture.

Thirty patients with lesions due to the rupture and repair of an aneurysm of the anterior communicating artery were compared neuropsychologically with 27 patients with ruptures but no lesions and 30 normal control subjects. Patients with combined lesions in the basal forebrain and striatum (n = 5), or basal forebrain, striatum, and ventral frontal cortex (n = 7), had severe memory deficits, whereas patients with lesions in the basal forebrain (n = 7) or the striatum (n = 5) alone showed virtually no deficits. Patients with lesions of the basal forebrain and ventral frontal cortex together (n = 6) showed mild memory deficits. In contrast to the memory effects, emotional changes were most pronounced in patients with striate lesions alone. Basal forebrain or ventral frontal lesions ameliorated rather than aggravated the emotional effects of striate lesions. It is suggested that the basal forebrain and the striatum form links of different pathways related to mnemonic information processing. Both systems may be able to compensate for a dysfunction of the other, but lesions of both systems together may lead to strong and unrecoverable memory deficits.

An analysis of the correlation of lesion size, localization and behavioral effects in 283 published studies of cortical and subcortical lesions in old-world monkeys.

The present article evaluates the quality and magnitude of the effects of lesion size and location and their interaction, on the behavioral performance of old world monkeys by a quantitative comparison of 283 published studies. The results indicate that lesion size alone is a poor predictor of the behavioral performance of monkeys, as opposed to Lashley's work in rats. Lesion location is a reliable predictor of the behavioral performance for brain regions thought to be primarily involved in a specific behavior; however, similar behavioral effects, although less reliable, can be observed for many different lesion loci, suggesting a specialized and a holistic brain functioning to be working at the same time. Some lesion loci are, in sharp contrast to current hypotheses about functional localization in the brain, not associated with impairments, but with significant improvements of a specific behavior. For such lesion loci the correlation of lesion size and behavioral performance may yield significant positive relationships (that is, increasing behavioral improvement with increasing lesion size); these relationships are contrasted by the significant negative relationships obtained for lesions of brain regions thought to be primarily involved in a given behavior. Thus, the lesion size may be a good predictor of the behavioral performance, depending on the lesion location and on the behavior under measurement. The behaviors analysed in this study were discrimination or delayed reaction or delayed matching-to-sample. The former two behaviors involve habit-like learning and are thought to be mediated by corticostriate functional pathways in the brain and the latter behavior implies the learning of single events, being thought to be mediated by corticolimbic functional pathways in the brain. Improved performances were observed for habit-like behaviors after lesions of brain regions (lateral frontal, premotor/motor, parietal, inferotemporal cortex, amygdala and fornix) being not primarily involved in a given behavior but possibly being able to inhibit the corticostriate pathways. Interestingly, lesions of subareas of the neostriatum were found to cause impairments in habit-like behaviors presumably being processed via these subareas (e.g. head of the caudate nucleus and delayed reaction), but to cause significant improvements in other behaviors (e.g. head of the caudate nucleus and visual discrimination). Thus, it may be concluded that diverse systems of functionally interconnected brain regions may maintain reciprocal inhibitions, with the result that a lesion within one system not only leads to a loss of one behavior, but in addition leads to a modification, may be a facilitation, of another behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional recovery after limbic lesions in monkeys.

Ten monkeys received lesions of either the hippocampus, or the amygdala and hippocampus, or the anterior and medial thalamus (each group with two monkeys), or of all these structures together with additional septal lesions (four monkeys). Postoperatively, the monkeys were trained in tasks of visual and spatial reversal, several concurrent object discriminations, delayed nonmatch-to-sample, and in an angle threshold discrimination task. Their performance was compared to that of five healthy or sham-operated control monkeys. The single- or double-lesioned monkeys were impaired in the delayed nonmatch-to-sample task and the angle threshold discrimination, whereas monkeys with five-fold lesions were unimpaired in these tasks. Correlations between brain volume loss and behavioral performance indicated negative coefficients for the delayed nonmatch-to-sample task ("delays": rs = -.59, "lists": rs = -.20) and the angle threshold discrimination (rs = -.60). It is concluded that monkeys with massive limbic lesions display a more effective postlesion reorganization than monkeys with smaller limbic lesions; however, reliability of this effect must be proved by future work with a larger sample. Furthermore, the missing impairments of massively lesioned monkeys especially in the delayed nonmatch-to-sample task also indicate that the limbic targets lesioned here may not be as exclusively involved in mnemonic information processing as suggested earlier.

Differential patterns of memory loss in patients with Alzheimer's disease and Korsakoff's disease.

Patients with Korsakoff's disease or the likely diagnosis of Alzheimer's dementia were tested on various mnemonic tasks and the results compared to the performance of alcoholic or normal controls. The experimental outcome indicates similar perceptual learning processes of Alzheimer and Korsakoff subjects. On the other hand, both groups of patients showed a somewhat different pattern of episodic memory loss, and a different proportion of intrusion and omission errors in the learning of semantically related words. The results are discussed with respect to some neuropathological and neuropsychological sequelae.

Cortical and subcortical afferent connections of the squirrel monkey's (lateral) premotor cortex: evidence for visual cortical afferents.

The afferent connections of the squirrel monkey's lateral premotor cortex were investigated with the horseradish peroxidase (HRP) technique. Seven monkeys received small, unilateral injections of HRP spaced between the most dorsal and the most lateral region of the premotor cortex. Results are based on six brains, all of which showed a considerable number of labeled neurons both cortically and subcortically. At the cortical level, labeled cells were found both ipsi- and contralateral to the injection site. Heavy labeling occurred in the fields surrounding the prefrontal, central, and precentral cortex, while the temporal regions usually innervated the premotor cortex with a moderate number of cells, and the parietal fields with only a minor number. Surprisingly, in all brains, but especially in those with the more lateral injections, we also found a considerable number of afferents originating from occipital fields, including a few neurons from the striate cortex. Subcortically, a few labeled cells were seen in basal forebrain regions, the amygdala, and the claustrum; a considerable number of thalamic nuclei and also some hypothalamic nuclei contained labeled cells; and within the brainstem, labeling was found most consistently in the locus ceruleus and in the tegmental fields. It is concluded that the (lateral) premotor cortex is involved in sensorimotor integration to a higher degree than has been recognized up to now.