Martin Ingvar

Central representation of chronic ongoing neuropathic pain studied by positron emission tomography.

&NA; This study was undertaken to explore whether the neural substrates demonstrated in brain imaging studies on experimentally induced pain are involved in the perception of chronic neuropathic pain. We investigated the cerebral representation of chronic lateralised ongoing pain in patients with painful mononeuropathy (PMN, i.e., pain in the distribution of a nerve, neuralgia) with positron emission tomography (PET), using regional cerebral blood flow (rCBF) as an index for neuronal activity. Eight patients (29–53 years) with PMN in the lower extremity (4 in the right, 4 in the left) were recruited. Paired comparisons of rCBF were made between the patients habitual pain (HP) state and the pain alleviated (PA) state following a successful regional nerve block (RNB) with lidocaine. The ongoing neuropathic pain resulted in activation of bilateral anterior insula, posterior parietal, lateral inferior prefrontal, and posterior cingulate cortices as well as the posterior sector of the right anterior cingulate cortex (ACC), Brodmann area (BA) 24, regardless of the side Of PMN. In addition, a reduction in rCBF was noted in the contralateral posterior thalamus. No significant change of rCBF was detected in the somatosensory areas, i.e., Sl and SII. The cerebral activation pattern, while addressing the differences between the HP and PA states, emphasises the affective‐motivational dimension in chronic ongoing neuropathic pain. The striking preferential activation of the right ACC (BA 24), regardless of the side of the PMN, not only confirms that the ACC participates in the sensorial/affectional aspect of the pain experience but also suggests a possible right hemispheric lateralisation of the ACC for affective processing in chronic ongoing neuropathic pain. Our data suggests that the brain employs different central mechanisms for chronic neuropathic pain and experimentally induced acute pain, respectively.

Pain-related cerebral activation is altered by a distracting cognitive task

Abstract It has previously been suggested that the activity in sensory regions of the brain can be modulated by attentional mechanisms during parallel cognitive processing. To investigate whether such attention‐related modulations are present in the processing of pain, the regional cerebral blood flow was measured using [15O]butanol and positron emission tomography in conditions involving both pain and parallel cognitive demands. The painful stimulus consisted of the standard cold pressor test and the cognitive task was a computerised perceptual maze test. The activations during the maze test reproduced findings in previous studies of the same cognitive task. The cold pressor test evoked significant activity in the contralateral S1, and bilaterally in the somatosensory association areas (including S2), the ACC and the mid‐insula. The activity in the somatosensory association areas and periaqueductal gray/midbrain were significantly modified, i.e. relatively decreased, when the subjects also were performing the maze task. The altered activity was accompanied with significantly lower ratings of pain during the cognitive task. In contrast, lateral orbitofrontal regions showed a relative increase of activity during pain combined with the maze task as compared to only pain, which suggests the possibility of the involvement of frontal cortex in modulation of regions processing pain.

Imaging cognitive modulation of pain processing.

The intensity and unpleasantness of a painful experience is often described as correlating well with the degree of noxious stimulation. However, the perception of pain is not a linear phenomenon, reflecting the signal from the peripheral neuron. Rather, the noxious input may be modulated at every level of the neural axis. One of the most potent sources of modulation is the brain—although these mechanisms have only sparsely been studied. The supraspinal modulatory influences involve both lower order automatic response schemata and higher order dynamic cognitive mechanisms. This organizational pattern has developed as an evolutionary driven adaptation, in which both fast hardwired responses and slower dynamic responses increased the chance for survival. In line with this hypothesis, it has been suggested that the brain is initially processing noxious input in the brainstem supporting the demand for a fast response (Petrovic et al., 2000a; Price, 2000). Apart from autonomic changes and a wide range of defense reactions, the brainstem may induce powerful analgesia in direct response to noxious stimuli (Fanselow, 1994). At a higher level, cognitive processes may dramatically modulate the perception of pain (Melzack and Casey, 1968; Weisenberg et al., 1996). Recently, functional imaging tools, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have described some of the possible underlying mechanisms that are involved in cognitive modulation of pain perception. Several functional imaging studies have indicated that pain processing may be modulated by cognitive mechanisms (Bantick et al., 2001; Longe et al., 2001; Petrovic et al., 2001a,b; Rainville et al., 1997, 1999; Willoch et al., 2000). Rainville and colleagues used hypnotic suggestion to modulate the perception of unpleasantness during noxious stimulation. When the subjects were suggested to perceive the noxious stimulation as highly unpleasant there was a concomitant increase in the activity in the anterior cingulate cortex (ACC) significantly more than when the subjects were suggested to perceive the same stimulation as less unpleasant (Rainville et al., 1997). However, the activity in the somatosensory areas was unaltered. Since lesion studies and animal studies have indicated that the ACC is involved in processing pain unpleasantness (Vogt et al., 1993) this finding indicates that cognitive mechanisms may specifically modulate sub-systems of the pain network. We used a different but classical approach in order to show that pain networks may be modulated by cognitive demands (Petrovic et al., 2000b). Most people have probably experienced that pain perception can decrease and even disappear when actively engaging the mind in a distracting task. We tested this mechanism by involving the subjects in a highly attention demanding task (computerized perceptual maze test) during noxious stimulation. We were able to show that when subjects solved the maze task and we induced a painful stimulation they perceived less pain as compared with when there was no competition for attentional space. At a neural level, activity was significantly attenuated in somatosensory regions and the PAG in this condition. Recently, it has been shown that cognitive distraction also may attenuate the pain-evoked activity in the ACC, the insula and the thalamus (Bantick et al., 2001; Longe et al., 2001). One intriguing study has demonstrated the opposite cognitive modulation in which the pain network was activated without any noxious stimulation being given (Willoch et al., 2000). In this study, painful perception was induced in patients with phantom-limb pain using hypnotic suggestion that the missing limb was in a painful position. All the regions discussed above are involved in pain processing, and modulation in their activity coincides with the changes in a pain perception. Apart from attention dependent changes in the network processing the perception, another distinct set of structures may act as sources for Pain 95 (2002) 1–5

Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study

Abstract Objective To determine whether exposure to low doses of ionising radiation in infancy affects cognitive function in adulthood. Design Population based cohort study. Setting Sweden. Participants 3094 men who had received radiation for cutaneous haemangioma before age 18 months during 1930-59. Main outcome measures Radiation dose to frontal and posterior parts of the brain, and association between dose and intellectual capacity at age 18 or 19 years based on cognitive tests (learning ability, logical reasoning, spatial recognition) and high school attendance. Results The proportion of boys who attended high school decreased with increasing doses of radiation to both the frontal and the posterior parts of the brain from about 32% among those not exposed to around 17% in those who received > 250 mGy. For the frontal dose, the multivariate odds ratio was 0.47 (95% confidence interval 0.26 to 0.85, P for trend 0.0003) and for the posterior dose it was 0.59 (0.23 to 1.47, 0.0005). A negative dose-response relation was also evident for the three cognitive tests for learning ability and logical reasoning but not for the test of spatial recognition. Conclusions Low doses of ionising radiation to the brain in infancy influence cognitive abilities in adulthood.

Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study

&NA; The study was conducted to investigate which areas of the brain respond to a painful encounter of minor dermal injury (a model of clinical pain)_elicited by intracutaneous injection of a minute amount of ethanol. Four healthy volunteers (27–46 years) were subjected to positron emission tomographic (PET) investigation of regional cerebral blood flow (rCBF), using [15O]butanol as tracer. The ethanol (20 &mgr;l, 70%) and saline (20 &mgr;l, 0.9%) were injected intracutaneously 3 times in a single‐blinded, semi‐randomised manner for the pain experiment. All the injections were performed, adjacent to each other, at the lateral aspect of the right upper arm. Subjective sensory intensity of pain, unpleasantness and anxiety were rated with separate 100‐mm visual analogue scales together with the Spielbergers State Anxiety Inventory (Spielberger et al. 1970) and heart rate. Paired‐subtraction (pixel‐by‐pixel) between ethanol and saline was performed. Traumatic pain significantly caused higher ratings of intensity and affect scales, i.e., pain intensity, unpleasantness and increased sympathetic activity (evidenced by tachycardia). In contrast the anxiety rating remained unchanged. Acute traumatic nociceptive pain prominently activated the hypothalamus and periaqueductal gray (PAG). In addition, activations of the prefrontal cortex (PFC), insular, anterior cingulate cortex (ACC), posterior parietal cortex (PPC), primary motor/somatosensory areas (MI/SI: face, upper arm), supplementary motor area (SMA), and cerebellum were also demonstrated. The central processing of the pain‐relevant/anticipatory arousal also engaged the PAG. This study demonstrates the involvement of the human cerebral cortex in perception, arousal, cognitive evaluative processes, and, hence, affective reactions (somatic/ autonomic outflow) associated with pain. The pain stimulus of traumatic character may, by its very nature, evoke the central processing to involve both the hypothalamus and the PAG.

The role of precuneus and left inferior frontal cortex during source memory episodic retrieval

The posterior medial parietal cortex and left prefrontal cortex (PFC) have both been implicated in the recollection of past episodes. In a previous study, we found the posterior precuneus and left lateral inferior frontal cortex to be activated during episodic source memory retrieval. This study further examines the role of posterior precuneal and left prefrontal activation during episodic source memory retrieval using a similar source memory paradigm but with longer latency between encoding and retrieval. Our results suggest that both the precuneus and the left inferior PFC are important for regeneration of rich episodic contextual associations and that the precuneus activates in tandem with the left inferior PFC during correct source retrieval. Further, results suggest that the left ventro-lateral frontal region/frontal operculum is involved in searching for task-relevant information (BA 47) and subsequent monitoring or scrutiny (BA 44/45) while regions in the dorsal inferior frontal cortex are important for information selection (BA 45/46).

Common prefrontal activations during working memory, episodic memory, and semantic memory

Regions of the prefrontal cortex (PFC) are typically activated in many different cognitive functions. In most studies, the focus has been on the role of specific PFC regions in specific cognitive domains, but more recently similarities in PFC activations across cognitive domains have been stressed. Such similarities may suggest that a region mediates a common function across a variety of cognitive tasks. In this study, we compared the activation patterns associated with tests of working memory, semantic memory and episodic memory. The results converged on a general involvement of four regions across memory tests. These were located in left frontopolar cortex, left mid-ventrolateral PFC, left mid-dorsolateral PFC and dorsal anterior cingulate cortex. These findings provide evidence that some PFC regions are engaged during many different memory tests. The findings are discussed in relation to theories about the functional contribution of the PFC regions and the architecture of memory.

Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study.

We used positron emission tomography (PET) to monitor the regional cerebral blood flow (rCBF) as an index of brain activity in regions proposed to participate in affective-motivational and cognitive-evaluative dimensions of pain during anticipation of a noxious stimulation. Specifically we were interested in the anterior cingulate cortex (ACC), the ventromedial prefrontal cortex (VMPFC) and the periaqueductal grey (PAG). Anticipating an unpredictable and unlearned pain stimulus activated the right ACC, the VMPFC and the PAG while anticipating a learned pain-stimulus resulted in a decreased activity in the ACC and the VMPFC. These patterns are compatible with two facets of affect-laden cognitive coping: alertness and attention-distraction. The right-preponderant expression of the changes in the ACC supports the hypothesis of a preferential role of the non-dominant hemisphere in negative emotional processing. The data demonstrate an anticipatory coping mechanism and illustrate a neurophysiological process underlying the modulation of attention to pain.

Enhancement by an Ampakine of Memory Encoding in Humans

Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans. Evidence for a positive influence on encoding was obtained in four tests: (i) visual associations, (ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv) location and identity of playing cards. The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory.

Neural correlates of training-related memory improvement in adulthood and aging

Cognitive studies show that both younger and older adults can increase their memory performance after training in using a visuospatial mnemonic, although age-related memory deficits tend to be magnified rather than reduced after training. Little is known about the changes in functional brain activity that accompany training-induced memory enhancement, and whether age-related activity changes are associated with the size of training-related gains. Here, we demonstrate that younger adults show increased activity during memory encoding in occipito-parietal and frontal brain regions after learning the mnemonic. Older adults did not show increased frontal activity, and only those elderly persons who benefited from the mnemonic showed increased occipito-parietal activity. These findings suggest that age-related differences in cognitive reserve capacity may reflect both a frontal processing deficiency and a posterior production deficiency.