Intraoperative recording of the very fast oscillatory activities evoked by median nerve stimulation in the human thalamus.
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Deep Brain Stimulation↗
Biomedical subjects
K D Davis
Publications and source records attributed to K D Davis.
Abnormal forebrain activity in functional bowel disorder patients with chronic pain.
BACKGROUND: Abnormal cortical pain responses in patients with fibromyalgia and conversion disorder raise the possibility of a neurobiologic basis underlying so-called "functional" chronic pain. OBJECTIVE: To use percept-related fMRI to test the hypothesis that patients with a painful functional bowel disorder do not process visceral input or sensations normally or effectively at the cortical level. METHODS: Eleven healthy subjects and nine patients with irritable bowel syndrome (IBS) underwent fMRI during rectal distensions that elicited either a moderate level of urge to defecate or pain. Subjects continuously rated their rectal stimulus-evoked urge or pain sensations during fMRI acquisition. fMRI data were interrogated for activity related to stimulus presence and to specific sensations. RESULTS: In IBS, abnormal responses associated with rectal-evoked sensations were identified in five brain regions. In primary sensory cortex, there were urge-related responses in the IBS but not control group. In the medial thalamus and hippocampus, there were pain-related responses in the IBS but not control group. However, pronounced urge- and pain-related activations were present in the right anterior insula and the right anterior cingulate cortex in the control group but not the IBS group. CONCLUSIONS: Percept-related fMRI revealed abnormal urge- and pain-related forebrain activity during rectal distension in patients with irritable bowel syndrome (IBS). As visceral stimulation evokes pain and triggers unconscious processes related to homeostasis and reflexes, abnormal brain responses in IBS may reflect the sensory symptoms of rectal pain and hypersensitivity, visceromotor dysfunction, and abnormal interoceptive processing.
Adult↗
Cognitive modulation of pain-related brain responses depends on behavioral strategy.
Interactions of pain and cognition have been studied in humans and animals previously, but the relationship between such behavioral interactions and brain activity is unknown. We aimed to show using functional MRI (fMRI) how a cognitively demanding task (Stroop) modulates pain-related brain activations and conversely, how pain modulates attention-related activity. Reaction time data indicated two types of pain responders: subjects in the A group had a faster Stroop reaction time when pain was concomitant to the attention task, while those in the P group had a slower Stroop performance during painful stimulation. fMRI data obtained during Stroop performance with and without noxious stimulation were subjected to region of interest analyses. We first tested whether brain activity during painful median nerve stimulation was modulated by cognitive load. We next tested whether brain activity during the high conflict cognitive task was modulated by pain. Pain-related activity in three regions, primary (S1), and secondary (S2) somatosensory cortices, and anterior insula, was attenuated by cognitive engagement, but this effect was specific to the A group. Pain-related activations in the caudal and rostral anterior cingulate cortex (ACC) and ventroposterior thalamus were not modulated by cognitive load. None of the areas showing attention-related responses, including bilateral dorsolateral prefrontal and posterior parietal cortices, were modulated by pain. These findings suggest that cortical regions associated with pain can be modulated by cognitive strategies. Furthermore, the distinction of behavioral subgroups may relate to cognitive coping strategies taken by patients with chronic pain.
Adult↗
Abnormal rectal motor physiology in patients with irritable bowel syndrome.
A contentious issue is whether irritable bowel syndrome (IBS) patients have abnormal rectal motor physiology. Our aim was to determine whether IBS patients have abnormal rectal responses to low (urge producing) or high (pain producing) distension pressures. The IBS patients and healthy controls underwent five series of isobaric rectal distensions to examine volume-pressure relationships and rectal accommodation: (i) ascending stepwise distensions terminating upon report of moderate pain, (ii) phasic and (iii) tonic distensions at a single low pressure producing a moderate sensation of urge to defecate (iv) phasic and (v) tonic distensions at a single high pressure producing a moderate pain sensation. The IBS patients demonstrated a lower rectal volume-pressure ratio during repetitive single-pressure phasic distensions, and a slower rate of rectal accommodation during low (but not high) pressure tonic distensions. However, dynamic compliance during ascending stepwise distensions and the change in rectal volume during tonic distension were not significantly different from controls. Rectal abnormality was readily demonstrated by determining the volume-pressure ratio using a small number of repetitive single-pressure distensions, supporting the hypothesis that IBS patients have abnormal rectal motor physiology. We propose that a peripheral neuromuscular substrate may contribute to the pathogenesis of IBS.
Adult↗
Perceptual illusion of "paradoxical heat" engages the insular cortex.
Paradoxical heat (PH), the illusion of skin heat, accompanies many neurological disorders. Using the technique of percept-related functional MRI, we found a region of the right insular cortex specifically activated when subjects perceive a heat sensation in their right hand even though their skin temperature is cool or at neutral. This region was suppressed during mild skin cooling. We propose that this differential response is a manifestation of the role of the insula in signaling temperature perceptions regardless of the actual temperature of the skin. These findings suggest that a region within the insula has a complex role in heat perception, perhaps contributing to a specific, rather than general, thermosensory perception. These data provide insight to our basic understanding of normal and pathological thermosensory perceptions.
Adult↗
Altered central somatosensory processing in chronic pain patients with "hysterical" anesthesia.
OBJECTIVE: The authors hypothesized that central factors may underlie sensory deficits in patients with nondermatomal somatosensory deficits (NDSD) and that functional brain imaging would reveal altered responses in supraspinal nuclei. BACKGROUND: Patients with chronic pain frequently present with NDSD, ranging from hypoesthesia to complete anesthesia in the absence of substantial pathology and often in association with motor weakness and occasional paralysis. Patients with pain and such pseudoneurologic symptoms can be classified as having both a pain disorder and a conversion disorder (Diagnostic and Statistical Manual of Mental Disorders-IV classification). METHODS: The authors tested their hypothesis with functional MRI (fMRI) of brush and noxious stimulation-evoked brain responses in four patients with chronic pain and NDSD. RESULTS: The fMRI findings revealed altered somatosensory-evoked responses in specific forebrain areas. Unperceived stimuli failed to activate areas that were activated with perceived touch and pain: notably, the thalamus, posterior region of the anterior cingulate cortex (ACC), and Brodmann area 44/45. Furthermore, unperceived stimuli were associated with deactivations in primary and secondary somatosensory cortex (S1, S2), posterior parietal cortex, and prefrontal cortex. Finally, unperceived (but not perceived) stimuli activated the rostral ACC. CONCLUSIONS: Diminished perception of innocuous and noxious stimuli is associated with altered activity in many parts of the somatosensory pathway or other supraspinal areas. The cortical findings indicate a neurobiological component for at least part of the symptoms in patients presenting with nondermatomal somatosensory deficits.
Adult↗
Kinaesthetic neurons in thalamus of humans with and without tremor.
Increased afferent input may alter receptive field sizes, properties and somatotopographic representation in the cortex. Changes in the motor thalamus may also occur as a result of altered afferent input. Such plasticity has been implicated in both sensory and movement disorders. Using tremor as a model of augmented afferent input to kinaesthetic/deep neurons representing the shaking limbs, we studied the representation and properties of these neurons in human thalamus in patients with resting tremor (RestTr) from Parkinson's disease, patients with action- or posture-induced tremor (ActionTr), and patients without tremor (NoTr). Data were collected during stereotactic thalamotomy or insertion of deep brain stimulators for relief of pain or movement disorder. Using microelectrode recording, 58 kinaesthetic neurons responding to wrist and/or elbow movement were studied by mapping the receptive field, carefully isolating each joint during testing. There were no significant differences in the proportions of single and multijoint responsive neurons in the different patient groups (RestTr, ActionTr and NoTr). The borders between tactile-cutaneous, deep-kinaesthetic and voluntary cell representations in the thalamus were mapped in 74 patients and compared between the different tremor groups. A significant difference in kinaesthetic representation was found: both the RestTr and ActionTr groups had a significantly greater kinaesthetic representation than the NoTr patients. There was an expansion of kinaesthetic representation in patients with chronic increased afferent drive from tremor, without alteration in RF size. No decrease in tactile representation was found, suggesting that the increase in kinaesthetic representation does not occur at the expense of tactile representation. These data suggest that plasticity can occur at the thalamic level in humans and may contribute to the pathogenesis of tremor.
Action Potentials↗
Neural correlates of prickle sensation: a percept-related fMRI study.
The painful sensations produced by a laceration, freeze, burn, muscle strain or internal injury are readily distinguishable because each is characterized by a particular sensory quality such as sharp, aching, burning or prickling. We propose that there are specific neural correlates of each pain quality, and here we used a new functional magnetic resonance imaging (fMRI) method to identify time-locked responses to prickle sensations that were evoked by noxious cold stimuli. With percept-related fMRI, we identified prickle-related brain activations in the anterior cingulate cortex (ACC), insula, secondary somatosensory cortex (S2), prefrontal cortex (PFC), premotor cortex (PMC), caudate nucleus and dorsomedial thalamus, indicating that multiple pain, sensory and motor areas act together to produce the prickle sensation.
Brain↗
Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.
BACKGROUND: Fenfluramine hydrochloride was withdrawn from the market in September 1997 after reports of heart valve abnormalities in patients who used it. The prevalence of echocardiographic abnormalities and the clinical cardiovascular status of patients who received fenfluramine monotherapy remains uncertain. METHODS: A long-term, follow-up evaluation was undertaken in subjects who were randomly assigned to receive either fenfluramine hydrochloride (60 mg daily) or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular status was evaluated by echocardiography, medical history, and physical examination. RESULTS: From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable. No statistically significant differences were identified in the prevalence of aortic or mitral regurgitation by Food and Drug Administration criteria or by grade, aortic or mitral valve leaflet mobility restriction or thickening, elevated pulmonary artery systolic pressure, or abnormal left ventricular ejection fraction. No significant differences were demonstrated in cardiovascular status by physical examination, and no serious cardiac events were noted among fenfluramine-treated subjects. CONCLUSION: There was no evidence of drug-related heart disease up to 4.9 years after anorexigen therapy in subjects who were randomly assigned to receive fenfluramine at the recommended dose for up to 3 months.
Adolescent↗
The effect of task relevance on the cortical response to changes in visual and auditory stimuli: an event-related fMRI study.
Attention is, in part, a mechanism for identifying features of the sensory environment of potential relevance to behavior. The network of brain areas sensitive to the behavioral relevance of multimodal sensory events has not been fully characterized. We used event-related fMRI to identify brain regions responsive to changes in both visual and auditory stimuli when those changes were either behaviorally relevant or behaviorally irrelevant. A widespread network of "context-dependent" activations responded to both task-irrelevant and task-relevant events but responded more strongly to task-relevant events. The most extensive activations in this network were located in right and left temporoparietal junction (TPJ), with smaller activations in left precuneus, left anterior insula, left anterior cingulate cortex, and right thalamus. Another network of "context-independent" activations responded similarly to all events, regardless of task relevance. This network featured a large activation encompassing left supplementary and cingulate motor areas (SMA/CMA) as well as right IFG, right/left precuneus, and right anterior insula, with smaller activations in right/left inferior temporal gyrus and left posterior cingulate cortex. Distinct context-dependent and context-independent subregions of activation were also found within the left and right TPJ, left anterior insula, and left SMA/CMA. In the right TPJ, a subregion in the supramarginal gyrus showed sensitivity to the behavioral context (i.e., relevance) of stimulus changes, while two subregions in the superior temporal gyrus did not. The results indicate a role for the TPJ in detecting behaviorally relevant events in the sensory environment. The TPJ may serve to identify salient events in the sensory environment both within and independent of the current behavioral context.
Adult↗
Sensory and affective components of orofacial pain: is it all in your brain?
In this paper, we shall review several chronic orofacial pain conditions with emphasis on those that are essentially refractory to treatment. We shall present a review of current and past literature that describes the various pain phenomena as well as their underlying central mechanisms. New data concerning refractory pain will be used to underscore the importance of central processing of pain, with particular emphasis on neuropsychological and cognitive function and capacity that may play important roles in pain processing and maintenance of the pain state. Further, neurophysiological data showing that the anterior cingulate cortex (ACC) and other structures in the brain may play key roles in modulation of chronic pain will also be discussed. Although peripheral triggering events surely play an important role in initiating pain, the development of chronic and, in particular, refractory pain may depend on changes or malfunctions in the central nervous system. These changes may be quite subtle and require sophisticated approaches, such as functional MRI, to study them, as is now being done. New findings obtained therefore may lead to more rational and reliable treatment for orofacial pain.
Accidents, Traffic↗
Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities.
BACKGROUND: The combination of fenfluramine and phentermine was a widely used obesity treatment before the withdrawal of fenfluramine for an association with heart valve regurgitation. The prevalence and clinical significance of regurgitation among patients treated with these medications has yet to be fully established. METHODS AND RESULTS: To evaluate the potential association between the duration of treatment and the prevalence of heart valve abnormalities, we examined 1163 patients who had taken fenfluramine-phentermine and 672 control patients who had not taken the drug combination within 5 years. Mild or greater aortic regurgitation was present in 8.8% of treated patients and 3.6% of control patients (P<0.001). Moderate or greater mitral regurgitation was present in 2.6% of treated patients and 1.5% of control patients (P=0.18). The adjusted odds ratio compared with controls of aortic regurgitation of mild or greater severity increased according to duration of treatment: 90 to 180 days, 1.5 (P=0.23); 181 to 360 days, 2.4 (P=0.002); 361 to 720 days, 4.6 (P<0.001); >720 days, 6.2 (P<0.001). CONCLUSIONS: This is the largest study to demonstrate a relation between the length of treatment with fenfluramine-phentermine and the prevalence of valvular abnormalities. These findings suggest that valvular abnormalities in patients who took fenfluramine-phentermine primarily involve those who had taken these medications for >6 months and predominantly results in mild aortic regurgitation. The valve regurgitation identified by this study was not accompanied by significant differences in cardiovascular symptoms nor physical findings other than a higher prevalence of heart murmurs.
Aortic Valve Insufficiency↗
Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine.
CONTEXT: Fenfluramine and dexfenfluramine were voluntarily withdrawn from the market in September 1997 because of reports of an association with heart valve abnormalities. Studies have been limited by lack of comparison with untreated controls. OBJECTIVE: To evaluate cardiovascular status and the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echocardiography, in patients treated for obesity with dexfenfluramine or phentermine/fenfluramine. DESIGN: Reader-blinded controlled study completed in February 1998. SETTING AND PARTICIPANTS: Twenty-five clinical centers in the United States. Of 1640 enrolled subjects, 1473 were eligible (479 and 455 had taken dexfenfluramine and phentermine/fenfluramine, respectively, continuously for 30 days or more in the previous 14 months, and 539 were untreated matched controls) and provided clinical and echocardiographic data. Mean (SD) age was 47.4 (11.4) years, mean body mass index was 35.0 (7.4) kg/m2, and 74% were women. Mean (SD) duration of therapy was 6.0 (3.3) months (range, 1-18.4 months) in the dexfenfluramine group, and 11.9 (10.4) months (range, 1.4-63 months) in the phentermine/fenfluramine group, while the untreated group had no anorexigen use during the previous 5 years. MAIN OUTCOME MEASURES: Cardiovascular signs and symptoms; echocardiographic evidence of aortic (AR) or mitral (MR) regurgitation according to US Food and Drug Administration (FDA) criteria (AR > or = mild or MR > or = moderate) and by grade; tricuspid and pulmonic valve regurgitation; and aortic, mitral, and tricuspid valve leaflet mobility and thickness, for treated vs untreated subjects. RESULTS: Cardiovascular signs and symptoms were similar among anorexigen-treated and untreated subjects. Prevalence rates and relative risk (RR) of AR were significantly increased in anorexigen-treated patients and were 8.9% in the dexfenfluramine group (RR, 2.18; 95% confidence interval [CI], 1.32-3.59), 13.7% in the phentermine/fenfluramine group (RR, 3.34; 95% CI, 2.09-5.35), and 4.1% in the untreated group (P<.001). No statistically significant differences in prevalence were observed for MR, thickening or decreased mobility of any valve leaflet, calculated pulmonary artery systolic pressure, or left ventricular ejection fraction. Serious cardiac events (including myocardial infarction, congestive heart failure, or ventricular arrhythmia) occurring at any time were not statistically different in treated and untreated subjects (dexfenfluramine, 9.0%; phentermine/fenfluramine, 4.0%; and untreated, 8.4%); and following anorexigen treatment were uncommon (dexfenfluramine, 2.3%; phentermine/fenfluramine, 2.4%, and untreated, 3.3%, when adjusted for the median start date of anorexigen use). CONCLUSIONS: Our data indicate that use of dexfenfluramine and phentermine/fenfluramine is associated with an increase in the prevalence of AR using FDA echocardiographic criteria, but was not associated with an increase in the prevalence of MR using FDA criteria or with serious cardiac events.
Aortic Valve Insufficiency↗
A multimodal cortical network for the detection of changes in the sensory environment.
Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.
Adolescent↗
The neural circuitry of pain as explored with functional MRI.
Since the discovery in the early 1990s that magnetic resonance imaging (MRI) can be used for functional imaging of the human brain, the technique has been used to examine the contribution of thalamic and cortical areas to the human pain experience. In a series of studies in this laboratory, functional MRI (fMRI) of noxious heat-, cold-, and median nerve stimulation-evoked activations demonstrated the involvement of the thalamus and multiple cortical areas in pain. The cortical areas identified included the primary and secondary somatosensory cortex (S1, S2), the anterior insula and the anterior cingulate cortex. The data also revealed a significant intersubject variability in the activation of any one of these regions, particularly during heat- and cold-evoked pain. These findings revealed the widespread cortical regions that are recruited by a noxious stimulus and provide clues to the neural circuitry of pain that undoubtedly include sensory, motor and cognitive components.
Brain↗
Human anterior cingulate cortex neurons modulated by attention-demanding tasks.
Recent imaging studies have implicated the anterior cingulate cortex (ACC) in various cognitive functions, including attention. However, until now, there was no evidence for changes in neuronal activity of individual ACC neurons during performance of tasks that require attention and effortful thought. We hypothesized these neurons must exist in the human ACC. In this study, we present electrophysiological data from microelectrode single neuron recordings in the human ACC of neuronal modulation during attention-demanding tasks in 19% of 36 neurons tested. These findings provide the first direct evidence of an influence of a cognitive state on the spontaneous neuronal activity of human ACC neurons.
Adult↗
Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study.
OBJECT: Deep brain stimulation (DBS) of the sensory thalamus has been used to treat chronic, intractable pain. The goal of this study was to investigate the thalamocortical pathways activated during thalamic DBS. METHODS: The authors compared positron emission tomography (PET) images obtained before, during, and after DBS in five patients with chronic pain. Two of the five patients reported significant DBS-induced pain relief during PET scanning, and the remaining three patients did not report any analgesic effect of DBS during scanning. The most robust effect associated with DBS was activation of the anterior cingulate cortex (ACC). An anterior ACC activation was sustained throughout the 40 minutes of DBS, whereas a more posteriorly located ACC activation occurred at a delay after onset of DBS, although these activations were not dependent on the degree of pain relief reported during DBS. However, implications specific to the analgesic effect of DBS require further study of a larger, more homogeneous patient population. Additional effects of thalamic DBS were detected in motor-related regions (the globus pallidus, cortical area 4, and the cerebellum) and visual and association cortical areas. CONCLUSIONS: The authors demonstrate that the ACC is activated during thalamic DBS in patients with chronic pain.
Adult↗
Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor.
Six patients undergoing stereotactic procedures for essential tremor received microinjections of muscimol (a gamma-aminobutyric acid-A [GABA(A)] agonist) into the ventralis intermedius thalamus in areas where tremor-synchronous cells were identified electrophysiologically with microelectrode recordings and where tremor reduction occurred with electrical microstimulation. Injections of muscimol but not saline consistently reduced tremor in each patient. The effect had a mean latency of 7 minutes and lasted an average of 9 minutes. We propose that GABA-mediated thalamic neuronal inhibition may represent a mechanism underlying the effectiveness of surgery for tremor and that GABA analogues could potentially be used therapeutically.
Aged↗