A visual learning and memory test for preoperative evaluation of patients with temporal lobe epilepsy.

We used a modified version of the visual DCS (mDCS) test to study patterns of learning, free recall, and recognition capacity in patients with temporal lobe epilepsy (TLE) (N = 24) and controls (N = 38). The patients were under consideration for epilepsy surgery. The mDCS differentiated left from right TLE patients in all aspects of visuospatial learning and delayed recall. The mDCS revealed lower performance for TLE patients as compared with controls. The present results indicate that the mDCS may be a preoperative tool to differentiate left from right TLE.

Neuroimmune relations in patients with fibromyalgia: a positron emission tomography study.

To study relations between neural and immune activity in patients with chronic pain, we correlated regional cerebral blood flow measured with [(15)O]butanol positron emission tomography to immune function in five patients with fibromyalgia. Partly replicating previous data in healthy volunteers, natural killer cell activity correlated negatively with right hemisphere activity in the secondary somatosensory and motor cortices as well as the thalamus. Moreover, natural killer cell activity was negatively and bilaterally related to activity in the posterior cingulate cortex. Thus, immune parameters were related to activity in brain areas involved in pain perception, emotion, and attention. Implicated from a small study population, these strong neuro-immune associations are discussed in view of recent findings concerning mechanisms and adaptive values in immuno-cortical communication and regulation.

Brain representation of habituation to repeated complex visual stimulation studied with PET.

To investigate CNS habituation (i.e. response decrement due to stimulus repetition) the present study used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in eight healthy women during two repetitions of complex visual stimuli. Repeated visual stimulation resulted in neural habituation bilaterally in the secondary visual cortex and in the right medial temporal cortex including the amygdala and the hippocampus. Regional CBF in the left thalamus was elevated as a function of repeated stimuli presentations. Thus, repeated presentation of complex visual stimuli result in rCBF habituation in later stages of the visual processing chain. The elevated neural activity in the thalamus might be associated with interruption of further neural transmission related to suppression of non-meaningful behavior.

Functional anatomy of hypnotic analgesia: a PET study of patients with fibromyalgia.

Hypnosis is a powerful tool in pain therapy. Attempting to elucidate cerebral mechanisms behind hypnotic analgesia, we measured regional cerebral blood flow with positron emission tomography in patients with fibromyalgia, during hypnotically-induced analgesia and resting wakefulness. The patients experienced less pain during hypnosis than at rest. The cerebral blood-flow was bilaterally increased in the orbitofrontal and subcallosial cingulate cortices, the right thalamus, and the left inferior parietal cortex, and was decreased bilaterally in the cingulate cortex. The observed blood-flow pattern supports notions of a multifactorial nature of hypnotic analgesia, with an interplay between cortical and subcortical brain dynamics. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Human brain-immune relationships: a PET study.

To study brain-immune relations, we correlated positron emission tomographic (PET) measures of regional cerebral blood flow (rCBF) with immune measures in 10 female volunteers. The natural killer (NK) activity correlated negatively with activity bilaterally in the secondary sensory cortex, whereas the Concanavalin A (Con A) response correlated positively with rCBF bilaterally in secondary visual, motor, and sensory cortices, the thalamus, the putamen, and the left hippocampus. Although representing preliminary data from a small number of subjects, these observations provide further support for the presence of interactions between the brain and the immune system.

Evidence of altered cerebral blood-flow relationships in acute phobia.

Functional cerebral guiding and integrating systems may be revealed by analyzing the covariation of regional cerebral blood flow (rCBF). Positron emission tomography (PET) was used to measure absolute rCBF in 14 volunteers with specific phobia and 6 nonphobic controls, when exposed to videos containing phobia-relevant and neutral scenes. A fear reaction and increased covariation between absolute rCBFs was observed during phobia-relevant as compared to neutral stimulation in phobics only. In controls fear was not elicited and rCBF covariation was not influenced by stimulus condition, being similar to the pattern observed in phobics during neutral stimulation. We suggest the rCBF correlative pattern during phobic fear to reflect fear-related activation of distinct neuronal pathways that involves the amygdala, the thalamus, and the striatum. We theorize that these pathways are activated also by uncontrolled emotions in diverse conditions, like posttraumatic stress disorder, panic disorder, and schizophrenia.

Magnetic brain imaging of extinction processes in human classical conditioning.

By recording neuromagnetic events during aversive classical conditioning, we examined the extinction of a previously described conditioned response. Averaging over non-reinforced exposures to the conditioned stimulus revealed magnetic activity in the secondary somatosensory and insular cortices, appearing between 110 and 140 ms after the omitted unconditioned electric shock. We suggest this activity to be elicited by the discrepancy between shock expectancy and perceptual processes associated with the omission of the unconditioned stimulus, reflecting one of several brain processes in extinction.

Parental history, aversive exposure and the development of snake and spider phobia in women.

Parental history and experiential factors in the development of snake and spider phobia were studied. Phobic women (DSM-IV, n = 158) reported on family history of animal phobia and whether direct (being frightened by the phobic object) or indirect (seeing someone else being frightened by and/or being warned of the phobic object) fear exposure predated phobia development. Fifty-nine mothers (37%) and 11 fathers (7%) had snake or spider phobia, which is higher than the upper 95% confidence interval in the populations (Fredrikson, Annas, Fischer & Wik, Behavior Research and Therapy, 34, 33-39). Lifetime Relative Risk, RR, of animal phobia in probands' mother and fathers as a function of at least one phobic grandparent was 3.3 and 13.7 respectively. Indirect fear exposures were more common in snake (45%) than spider (27%) phobics (RR = 1.4). Indirect fear exposures were more common among probands with a positive parental history, the RRs being 3.6 and 2.1 as a function of maternal and paternal family history. Direct exposures were unrelated to parental history. The familial resemblance and transmission of specific phobia could be experiential in origin mediated by indirect exposures or of hereditary origin mediated by genetic factors. It may represent genetically facilitated learning and exemplify imprinting in humans.

Cerebral blood flow during anxiety provocation.

It has been suggested that traumatic reactions result from the failure to integrate the trauma with existing cognitive schemata, whereas phobias represent biologically influenced adaptation patterns. This implies that central nervous system (CNS) organization of traumatic reactions may differ from that of phobic reactions. In this article, we review our previously published work on anxiety and regional cerebral blood flow (rCBF). By using positron emission tomography and [(15)O]-butanol, relative rCBF was determined in 14 subjects with simple animal phobias exposed to visual phobogenic stimuli and in 6 bank officials exposed to a video showing an armed bank robbery that they recently witnessed. Subjective and physiologic indices of fear and anxiety were elevated by the activation condition in both groups. Phobic stimulation elevated rCBF bilaterally in the secondary visual cortex compared with neutral stimulation but reduced rCBF in the hippocampus and in the prefrontal, orbitofrontal, temporopolar, and posterior cingulate cortex. Compared with neutral stimulation, video of a robbery increased rCBF bilaterally in the primary and secondary visual cortex, the posterior cingulate, and the left orbitofrontal cortex. Decreased rCBF was evident in Broca's area, the left angular gyrus, the left operculum, and the secondary somatosensory cortex. Hence, visually induced fear and anxiety are associated with alterations in limbic, paralimbic, and cortical brain regions that are of relevance for cognition and affect.

The amygdala and individual differences in human fear conditioning.

While animal research on fear conditioning suggests crucial involvement of the amygdala, this has not been corroborated in humans when using subtractive neuroimaging methodology. Correlation analyses might be more able to reveal relations between individual differences in conditionability and central neural activity. Hence, we performed a directed search for amygdalar participation in human fear conditioning by correlating central and autonomic nervous activity. [15O]Butanol positron emission tomography evaluated regional cerebral blood flow (rCBF) in six subjects before and after aversive conditioning to visual snake stimuli. Non-specific electrodermal fluctuations (EDA) were recorded simultaneously. A significant positive correlation was obtained between conditioned EDA and conditioned rCBF in the right amygdala (r = 0.75, p < 0.05), supporting involvement of the amygdala in human fear conditioning.

Cerebral correlates of anticipated fear: a PET study of specific phobia.

Cerebral correlates of anticipatory anxiety was studied in 14 women with specific snake or spider phobia, and in 6 nonphobic controls. Videofilms with neutral scenes were shown during positron emission tomographic measurements of regional cerebral blood flow (rCBF). The phobics, but not the controls, anticipated scenes with spiders or snakes to appear in the videofilms. This was reflected in higher anxiety ratings in the phobics. The primary visual cortex rCBF was lower in phobics than controls, while no rCBF differences were found in the other brain regions investigated. The results are suggested to indicate inhibition of corticogeniculate pathways, in turn representing a neurophysiological correlate of avoidant anticipatory coping.

Functional neuroanatomy of robbery re-experience: affective memories studied with PET.

Using positron emission tomography (PET) and [15O]butanol, regional cerebral blood flow (rCBF) was determined in six bank officials during exposure to a video of a jointly experienced armed bank robbery, and a control video. Besides elevating subjective and physiological indices of anxiety, traumatic stimulation increased rCBF bilaterally in the primary and secondary visual cortex, the posterior gyrus cinguli and in the left orbitofrontal cortex compared with that during the control stimulation. Decreased rCBF was found in Broca's area, the left angular gyrus, the left operculum and the secondary somatosensory cortex. Thus, the stress induced by visual re-experience of a robbery is associated with altered activity in paralimbic and cortical brain regions of relevance for cognition and affect.

Magnetic imaging in human classical conditioning.

Magnetoencephalography (MEG) was recorded during aversive classical conditioning in an attempt to elucidate the temporal coding of primary somatosensory cortex (SI) activation previously found with positron emission tomography. Four healthy volunteers participated in the experiment. The reinforced conditioned stimulus was displayed on a screen for 2 s, and as it disappeared an unconditioned electric shock to the right middle finger followed. A control stimulus, not paired with a shock was also presented. With MEG, we observed a conditioned magnetic response located in the SI. The conditioned response predated the shock presentation and is interpreted as evidence for functional control of nociception mediated by corticothalamic projections.

Gender and age differences in the prevalence of specific fears and phobias.

Point prevalence of specific fears and phobias was determined in 704 respondents of 1000 randomly selected adults aged 18-70 yr. A phobia for lightning, enclosed spaces, darkness, flying, heights, spiders, snakes, injections, dentists and/or injuries was defined if subjects reported a fear that was out of conscious control, interfered with life and lead to the avoidance of the feared object [American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edn). Washington, DC: American Psychiatric Press.] Fear intensity was assessed using visual analogue scales. A factor analysis generally supported the classification of fears and phobias into: (1) situational phobias (lightning, enclosed spaces, darkness, flying and heights); (2) animal phobias (spiders and snakes); and (3) mutilation phobias (injections, dentists, injuries). Total point prevalence of any specific phobia was 19.9% (26.5% for females and 12.4% for males). In total, 21.2% women and 10.9% men met criterias for any single specific phobia. Multiple phobias was reported by 5.4% of the females and 1.5% of the males. Animal phobia had a prevalence of 12.1% in women and 3.3% in men. Point prevalence of situational phobia was 17.4% in women and 8.5% in men. For mutilation phobia no gender difference was observed, being presented in 3.2% of the women and 2.7% of the men. Women as compared to men gave higher fear ratings for all objects and situations. Inanimate object fears and phobias were more common in older than younger individuals. Animal fears were more intense in younger than in older individuals. Fear of flying increased and fear of injections decreased as a function of age in women but not in men. Thus, specific fears and phobias are heterogeneous with respect to sex and age distribution.

Affective and attentive neural networks in humans: a PET study of Pavlovian conditioning.

Using positron emission tomography (PET) and [15O]butanol we studied regional cerebral blood flow (rCBF) to a visual snake stimulus before and after classical conditioning with an unconditioned electric shock delivered to the right hand. Measures of heart rate, electrodermal activity, state anxiety and subjective distress confirmed classical conditioning of physiological and subjective responses. Subcortically, conditioning increased rCBF bilaterally in the ventromedial thalamus, the posterior hypothalamus and the central grey of the midbrain. Cortically, rCBF increased in the left anterior and posterior cingulate gyrus, the left primary somatosensory cortex, the left premotor cortex and bilaterally in parietal areas. Thus, the functional organization of classical conditioning in humans involves autonomic, affective and attentive brain mechanisms.

Effects of neuroleptic treatment on cortisol and 3-methoxy-4-hydroxyphenylethyl glycol levels in blood.

Plasma cortisol and serum 3-methoxy-4-hydroxyphenylethyl glycol (MHPG) were determined before and after 5-6 weeks of neuroleptic treatment in patients with schizophrenia. Following drug treatment both plasma cortisol and serum MHPG levels in patients decreased and plasma cortisol levels were also lower than in unmedicated healthy controls. Indications of a relationship between the reduction of cortisol and MHPG levels were found. The data show that neuroleptic drug treatment inhibits cortisol secretion. It is speculated that this inhibition could be related to reduced noradrenergic activity.

Functional neuroanatomy of visually elicited simple phobic fear: additional data and theoretical analysis.

We investigated central nervous system correlates of simple phobic fear. Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) in eight volunteers with symptomatic spider phobia that were exposed to visual phobogenic and neutral stimuli. Diazepam (0.1 mg/kg body weight i.v.) or placebo was administered under double-blind conditions after initial PET scans. The PET scans were then repeated. The presence of fear was confirmed by rating procedures and increased number of nonspecific electrodermal fluctuations and by higher heart rate during phobic than during neutral stimulation. Phobic as compared to neutral stimulation elevated the regional to whole brain (relative) CBF in the secondary visual cortex but reduced relative rCBF in the hippocampus, prefrontal, orbitofrontal, temporopolar, and posterior cingulate cortex. Diazepam treatment did not affect the relative rCBF or the subjective or physiological fear indices. The observed rCBF pattern replicates our previous findings in snake phobics (M. Fredrikson et al. [1993] Psychophysiology, 30, 127-131; G. Wik et al. [1993] Psychiatry Research (Neuroimaging), 50, 15-24) and indicates that fear and anxiety affect cortical areas outside the classic limbic system areas.

Neural networks in chemotherapy-induced delayed nausea - a pilot-study using positron emission tomography.

Acute but not delayed nausea is well controlled by serotonergic receptor-antagonists implicating different mediation of delayed as compared to acute nausea and vomiting. We report on differences in central neural activity using positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) in two chemotherapy treated cancer patients during delayed severe and mild nausea. Subtractive image methodology where rCBF during moderate nausea was subtracted from rCBF during mild nausea revealed increased neural activity in the anterior hypothalamus, the vermis, the anterior cingulate gyrus and the thalamus as well as decreased activity in the pens and the substantia nigra. These results may reveal central nervous system substrates underlying delayed nausea and vomiting and are consistent with an interpretation in terms of activation both of serotonergic and noradrenergic but not dopaminergic transmitter systems. It is concluded that noradrenergic mediation of delayed nausea is not an unlikely possibility.

A functional cerebral response to frightening visual stimulation.

The defense reaction, a fundamental reflex in the human behavioral response to threat, is characterized by anxiety and increased activity of the sympathetic nervous system. To study changes in regional cerebral blood flow (rCBF) related to the defense reaction, volunteers with snake phobia were investigated with positron emission tomography. The relative rCBF during phobogenic visual stimulation was increased in the secondary visual cortex but reduced in the hippocampus, orbitofrontal, prefrontal, temporopolar, and posterior cingulate cortex compared with that observed during neutral visual stimulation. The relative rCBF under aversive stimulation was intermediate between phobic and neutral stimulation. The rCBF patterns observed are suggested to represent a functional cerebral correlate to the visually elicited defense reaction and its associated emotions.