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.

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.

Cortical projections originating from the cat's insular area and remarks on claustrocortical connections.

The cortical projections originating in the cat's insular cortex and claustrum were investigated with the aid of the horseradish peroxidase retrograde tracing technique. Twenty small injections of horseradish peroxidase were distributed along lateral and medial regions of the hemisphere. Labeling in the insular cortex occurred following all injections except those six situated along the lateral gyrus--that is, within the visual cortex. In the claustrum labeled neurons were found following all injections, except following the injection situated in the posterior temporal area. Claustral labeling was frequently more intense than insular labeling. The injections into the occipital cortex that revealed no insular innervation nevertheless received a considerable number of claustral projections. As the insular cortex itself receives at most a minor projection from the claustrum the differing cortical projection patterns of insula and claustrum have to be considered unrelated. Our findings confirm the view that the claustrum projects to most regions of the cerebral cortex; these projections are at least in part topographically organized. A topographical pattern can also be constructed for the insular cortex, though it is less stringent than for the claustrocortical connections. Both the afferent and efferent connections of the insula show similarities to those of the prefrontal cortex. Nevertheless, the insula differs in that it receives strong input from the sensory associative nuclei of the thalamus. Consequently, and in line with behavioral observations following its ablation, we consider the insula as involved in the temporal structuring of perceived patterns.

Cortical and subcortical afferent connections of the primate's temporal pole: a study of rhesus monkeys, squirrel monkeys, and marmosets.

The afferent connections of the primate's temporopolar cortex were investigated with the retrograde horseradish peroxidase technique. Old World and New World monkeys received small unilateral injections of horseradish peroxidase. These labeled cells in a number of cortical, thalamic, and brainstem regions and in a few further telencephalic and diencephalic regions. Cortically, the neighboring areas of the inferior and superior temporal gyrus and the insula contained a considerable number of labeled cells. Furthermore, a substantial projection arose from the orbitofrontal and the frontopolar cortex. The cingulate gyrus contained only very few labeled cells. Interhemispherically, corticocortical connections arose mainly from temporal lobe areas. Labeled cells were seen in various regions of the basal forebrain and cells labeled only faintly in the lateral and basal accessory nuclei of the amygdala. The claustrum contained labeled neurons only in one rhesus monkey. On the diencephalic level, the caudal medial portion of the medial pulvinar was the principal thalamic source of afferents to the temporopolar cortex. Furthermore, labeled cells were found in the neighboring, caudal part of the mediodorsal nucleus, within and along the nucleus limitans, in the medial geniculate nucleus, and in several nuclei of the nonspecific system. The fields of Forel, the zona incerta, and lateral and dorsomedial hypothalamic areas contained a few labeled cells. Within the brainstem of the rhesus monkeys those regions projecting diffusely to the cortex contained a few labeled neurons. Furthermore, these brains had some labeled cells in the regions of the nuclei medialis annuli aqueductus, tractus mesencephalicus nervi trigemini, and trochlearis. Although among the three species differences in the cortical and thalamic projection patterns were observed, the regions projecting most densely to the temporal pole were similar in principle. This statement holds in particular for cortical and thalamic sites. However, the greatest number of labeled cells was found in the rhesus monkey, a fact that cannot be attributed solely to the size of the horseradish peroxidase injections and the size of the brain, but that appears rather to represent a true species difference. From our results we conclude that the temporopolar cortex constitutes a cortical area necessary for effective affectional-sensory integration.

Afferents to the ventral tegmental nucleus of Gudden in the mouse, rat, and cat.

Afferents to the ventral tegmental nucleus of Gudden (VT) were investigated in mice, rats, and cats. Unilateral and bilateral injections or iontophoretical applications of horseradish peroxidase (HRP) were made into the region of the VT. The entire cerebrum was then screened for labeled neurons. Following injections situated principally within the VT, in all three species many retrogradely labeled neurons were observed in the mamillary bodies and the lateral habenular nuclei. Fewer labeled cells were observed in the prefrontal cortex, the basal forebrain, various hypothalamic nuclei, the interpeduncular nucleus, nucleus of the posterior commissure, nucleus of Darkschewitsch and interstitial nucleus of Cajal, vestibular nucleus, and nucleus praepositus hypoglossi. Scant but consistent labeling occurred in the cingular, retrosplenial, and insular cortices, within the medial forebrain bundle, fields of Forel, zona incerta, ventral tegmental area of Tsai, substantia nigra, pretectal area, periaqueductal gray, dorsal tegmental nucleus, locus ceruleus, and raphe complex. Our results show a high similarity in the distribution of afferent connections converging on the VT of mice, rats, and cats. They indicate furthermore that the VT is reached by a variety of cortical and subcortical afferents, which belong either to the limbic system or to brain stem regions related to motor, sensory, and autonomic functions. It is suggested that the VT subserves as a midbrain core structure of the limbic system, which is responsible for the transfer of motor, sensory, and autonomic informations arising within the brain stem to limbic forebrain structures.

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.

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.

Korsakoff and alcoholic subjects are severely impaired in animal tasks of associative memory.

Korsakoff subjects, members of the Alcoholics Anonymous, and alcoholics with 1 week or 5-6 months of abstinence were tested in a concurrent object discrimination task with 10 and 20 pairs of objects and compared to control subjects matched for age and education. The anonymous alcoholics were moderately Korsakoff subjects strongly impaired, whereas alcoholics with 1 week or 5-6 months abstinence performed similar to control subjects. The results are discussed with respect to current research on human amnesia and comparative neuropsychological topics.

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.

Widespread cortical projections of the hippocampal formation in the cat.

Efferent projections from the hippocampal formation to the cat's cortex were traced with the retrograde horseradish peroxidase technique. Different areas of the cortex of 31 cats were injected with small amounts of horseradish peroxidase. All subregions of the hippocampal formation were screened for labeled cells. It was found that, with the exception of the entorhinal injections, only subicular areas of the hippocampal formation contain labeled neurons. When HRP was injected into the entorhinal cortex, labeled cells are also found in the hippocampus proper. The most dense projection from the subicular cortex is directed to the medial part of the cortical hemisphere. Here, cingulate, retrosplenial and medial prefrontal fields receive a substantial number of subicular efferents. Furthermore, the entorhinal cortex is reached by a number of axons originating in the subicular area. Scarce projections from the subicular cortex terminate in the dorsal prefrontal, temporal, parietal and prepiriform cortex. It is suggested that the projection from the subicular cortex to the neocortical areas of the frontal pole (medial prefrontal cortex) is of special importance as it may constitute a link between the association areas of the neocortex and those regions of the limbic system thought to play a role in memory (subicular cortex, mamillary bodies, anterior thalamus, cingulate gyrus).

Claustral efferents to the cat's limbic cortex studied with retrograde and anterograde tracing techniques.

The claustral projections to the cat's limbic cortex were investigated with horseradish peroxidase retrograde tracing technique and with autoradiography. Autoradiographic injections covered small portions of either the dorsal anterior claustrum or intermediate to posterior regions of the claustrum. Injections of horseradish peroxidase were made into the subicular, insular, entorhinal, prepiriform, cingulate, retrosplenial and prefrontal cortex. Both methods revealed fully consistent data for substantial claustral efferents to the cingulate, retrosplenial, entorhinal and subicular cortex. For the prepiriform cortex claustral efferents could be established unequivocally only with the horseradish peroxidase technique. Only a rather minor projection could be traced for the claustro-insular projection. Unilateral injections of horseradish peroxidase revealed the existence of a minor number of labeled claustral cells in the contralateral hemisphere for all loci except insular and prepiriform ones. Our data show that claustral cells reach the majority of the allocortical areas of the brain. They thereby confirm the view that the claustrum projects to most regions of the cortex and furthermore that a certain kind of topography exists in the claustro-cortical afferents with a minor number of claustral cells sending afferents to the contralateral cortical hemisphere. In addition, our data reveal that the distribution of claustro-cortical afferents is uneven and that the ventral claustrum (or nucleus endopiriformis) sends fibers to more cortical regions than previously assumed. It is suggested that the claustrum participates in the integration of sensory, motivational, emotional and mnemonic information via its reciprocal claustro-neocortical and its claustro-limbic connections.

Differential effects of double and triple lesions of the cat's limbic system on subsequent learning behavior.

On the basis of recent anatomical experiments in which it was found that the anterior thalamus, the subicular cortex, and the mamillary bodies are directly and strongly interconnected, lesions were made in different combinations of two or all three of these regions in four groups of cats. These found groups and a control group were then subjected to two learning tasks: a visual reversal and an active two-way avoidance task. Compared with cats of the control group, cats with lesions of the anterior thalamus and the mamillary bodies (Group AT/MM), of the anterior thalamus and the subiculum (Group AT/SUB), or of the mamillary bodies and the subiculum (Group MM/SUB) were strongly impaired in acquiring the reversal task, whereas cats with lesions of all three structures together (Group AT/MM/SUB) were unimpaired. Similarly, in the active avoidance task, two of the three groups with double lesions (MM/SUB; AT/SUB) were imparied, but cats of Groups AT/MM and AT/MM/SUB were not, compared with the control group. Consideration is made that lesion-induced shifts possibly act upon intact cortical and/or thalamic structures that, prior to massive limbic lesions, remained inhibited or otherwise suppressed. It is assumed the influence of one of the three core regions of the modified Papez-circuit to be sufficient for inhibiting the action of such structures which following a complete lesion of the system may control essential parts of the behaviors tested.

Differential effects of prefrontal lesions and combined prefrontal and limbic lesions on subsequent learning performance in the cat.

On the basis of a previous experiment (Irle & Markowitsch, 1983) in which triple limbic lesions as opposed to double limbic lesions in the cat failed to impair the learning behavior of these animals, the effects of a lesion in a fourth brain structure, in addition to the original ones, were examined. Two groups of cats were given lesions in either the prefrontal cortex alone or in the prefrontal cortex, the anterior thalamus, the mamillary bodies, and the subiculum and subsequently tested in the acquisition of a visual reversal, a delayed alternation, and an active two-way avoidance task. Compared with control cats, cats with prefrontal lesions were strongly impaired in the acquisition of the visual reversal task and the delayed alternation task but only slightly impaired in the acquisition of the active two-way avoidance task. In contrast, animals with combined prefrontal cortical, anterior thalamic, mamillary, and subicular lesions were unimpaired in the acquisition of the visual reversal task, slightly facilitated in the acquisition of the active two-way avoidance task, but impaired in the acquisition of the delayed alternation task similarly to the animals with prefrontal lesions. The superior performance rates of the animals with fourfold lesions are considered to be due to a lesion-induced functional shift acting on intact brain structures which, prior to massive limbic lesions, remain inhibited or otherwise suppressed. The failure of the animals with fourfold lesions in the delayed alternation task indicates that the functions underlying this type of behavior cannot be compensated for or, alternatively, that a prefrontal lesion is not sufficient to disinhibit other structures involved in the same behavior.

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.

Widespread neuroanatomical damage and learning deficits following chronic alcohol consumption or vitamin-B1 (thiamine) deficiency in rats.

Consequences of long-term consumption of alcohol (20 months) and of pyrithiamine-induced blockade of vitamin-B1-uptake on the shape of individual brain structures and on the acquisition of two learning tasks have been investigated in 3 groups of rats (alcohol group, AL; thiamine-deficient group, TH; control group, CG). Groups AL and TH wee allowed an 8, or 3 week recovery period, respectively, with normal food and water available ad libitum before behavioral testing started. This consisted of training an active two-way avoidance task and a spatial reversal task. Rats of both experimental groups were, compared to rats of the control group, significantly impaired in acquiring the avoidance task and in acquiring the original discrimination of the spatial reversal task. No differences were found among the two experimental groups. Histological and microscopical examinations of the brains of the rats with a history of thiamine-deficiency or of chronic alcohol consumption revealed a variety of severely affected brain areas. In both groups hippocampal and cerebellar damage was prominent. Furthermore, the mamillary nuclei, certain brainstem regions situated around the ventricles and a few cortical areas contained loss or damage of neurons. It is concluded that the anatomical changes, especially, can be related to those seen in chronic alcoholics and that consequently animal models can be established to investigate in detail the multiple interactions of alcohol consumption, thiamine deficiency, brain damage and behavioral deterioration.

Single and combined lesions of the cats thalamic mediodorsal nucleus and the mamillary bodies lead to severe deficits in the acquisition of an alternation task.

The acquisition of a spatial alternation task was tested in five groups of adult cats. Two groups were used for control; one of them consisted of nonlesioned cats, the other of cats with chemical lesions (ibotenic acid) of the ventral tegmental area. The other three groups of cats received chemical lesions of the mediodorsal nucleus of the thalamus, the mamillary bodies, or of both structures together. Cats with lesions of the ventral tegmental area were non-significantly impaired in comparison to non-lesioned cats in the acquisition of the task. Cats with lesions of the mediodorsal nucleus, the mamillary bodies, or with combined lesions of both structures were significantly impaired, compared to the two control groups; among each other, however, their performance rates were similar. As none of the cats with single or combined lesions of the mamillary and the mediodorsal nuclei manifested observable abnormalities with respect to motor, motivational, or emotional behavior during their testing period, it is concluded that their--compared to the other two groups--inferior performance was due to a memory defect. As all three kinds of lesions resulted in a similar defect, it is suggested that the mamillary and the mediodorsal nuclei transmit information to one or more common target area(s), which is (are) dependent on information from either nucleus to operate effectively.

Lesion size and recovery of function: some new perspectives.

The present article discusses the possibility that functional recovery following brain damage may be to a large degree dependent on the amount of nervous tissue destroyed, such that more neuronal destruction may lead to more and not (as commonly suggested) to less recovery. This assumption may derive from the neuropsychological and neurological literature: many cases with circumscribed brain lesions are implicated with severe functional losses. However, patients with dramatic and severe brain destructions often show astonishingly normal behavior regarding cognition, speech, visuospatial, motor and sensory functions. Animal experimentation as well shows that an extensive lesion of a brain area may be associated with equal or less functional detriment than a small lesion of the same area. Along with the well-known variables of age, lesion growth, or personality and environmental factors, the amount of tissue destroyed should be considered as a potent mediator of functional recovery. At least for some functions and brain regions, the likeliness of recovery may increase with the extent of the lesion and thus the necessity of the brain to fulfill plastic changes.

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.

The thalamic mediodorsal nucleus receives input from thalamic and cortical regions related to vision.

The mediodorsal nucleus of the thalamus (MD) so far has been regarded as being not closely connected to visual regions. Based on the method of retrograde transport of horseradish peroxidase, direct efferents to the cat's mediodorsal nucleus were demonstrated from two visual regions: from the ventral lateral geniculate nucleus and from parts of the visually responsive cortex. These projections were obtained following injections which covered most of MD, but also following injections which were restricted to medial or lateral parts and to the anterior two-thirds or merely to the center of MD. Projections from the ventral lateral geniculate nucleus arose mainly from its caudal portion; projections from the visually responsive cortex originated predominantly in area 20a, but labeled cells were also occasionally detected in areas 18 and 19.