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Biomedical subjects

H C Middleton

Publications and source records attributed to H C Middleton.

16 recordsLinked to original sources
PubMed1999

Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex.

Patients sustaining lesions of the orbital prefrontal cortex (PFC) exhibit marked impairments in the performance of laboratory-based gambling, or risk-taking, tasks, suggesting that this part of the human PFC contributes to decision-making cognition. However, to date, little is known about the particular regions of the orbital cortex that participate in this function. In the present study, eight healthy volunteers were scanned, using H(2)(15)0 PET technology, while performing a novel computerized risk-taking task. The task involved predicting which of two mutually exclusive outcomes would occur, but critically, the larger reward (and penalty) was associated with choice of the least likely outcome, whereas the smallest reward (and penalty) was associated with choice of the most likely outcome. Resolving these "conflicting" decisions was associated with three distinct foci of regional cerebral blood flow increase within the right inferior and orbital PFC: laterally, in the anterior part of the middle frontal gyrus [Brodmann area 10 (BA 10)], medially, in the orbital gyrus (BA 11), and posteriorly, in the anterior portion of the inferior frontal gyrus (BA 47). By contrast, increases in the degree of conflict inherent in these decisions was associated with only limited changes in activity within orbital PFC and the anterior cingulate cortex. These results suggest that decision making recruits neural activity from multiple regions of the inferior PFC that receive information from a diverse set of cortical and limbic inputs, and that the contribution of the orbitofrontal regions may involve processing changes in reward-related information.

Adult↗
PubMed1999

Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour.

RATIONALE: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking. However, little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour. OBJECTIVES AND METHODS: We compared the effects of rapid plasma tryptophan depletion, acute doses of the mixed indirect catecholamine agonist, methylphenidate (40 mg), and acute doses of the alpha(1)/alpha(2 )agonist, clonidine (1.5 microg/kg), on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions. RESULTS: Relative to subjects who received placebo, subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations, but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension. By contrast, subjects who received methylphenidate were able to learn effectively about changing stimulus-reward associations, but showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes. CONCLUSIONS: These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions (e.g. orbitofrontal cortex, striatum and anterior temporal structures) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value. On the other hand, facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment, perhaps through altered modulation of the dorsolateral prefrontal cortex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.

Adolescent↗
PubMed1999

Idazoxan potentiates rather than antagonizes some of the cognitive effects of clonidine.

Several investigations have revealed substantial influences of pharmacological manipulation of central noradrenergic activity upon performance in cognitive tests sensitive to frontal lobe dysfunction. They suggest a significant role for the noradrenergic coeruleo-cortical projection in cognitive function but conflicting findings and the complex pharmacology of adrenoceptor agents make it difficult to be precise about underlying mechanisms. In order to clarify these we have compared the effects of an alpha1/alpha2-adrenoceptor agonist, clonidine, an alpha2-adrenoceptor antagonist, idazoxan, and these agents in combination. Three groups of healthy volunteers were used to investigate the effects of these noradrenergic manipulations upon performance of tasks from the CANTAB test battery known to be sensitive to frontal lobe dysfunction. Previously reported effects of clonidine upon sustained visual attention and upon session-to-session improvement were replicated. Furthermore, idazoxan inhibited the hypotensive effect of clonidine. Idazoxan had no overall effect on performance of any of the tests but did inhibit session-to-session improvement in performance of a planning task, attentional set shifting and sustained visual attention. Rather than leading to the anticipated mutual antagonism of effects, combining clonidine and idazoxan led to a wider and more striking range of cognitive impairments. These results are discussed alongside findings which support a role for imidazoline (I1) receptors in blood pressure control, where clonidine and idazoxan are antagonistic, and evidence of less potent antagonism at somato-dendritic alpha2-adrenoceptors in the locus coeruleus.

Adrenergic alpha-Agonists↗
PubMed1999

Contrasts between the cardiovascular concomitants of tests of planning and attention.

Physiological response stereotypy is a well-established psychophysiological construct. Unfortunately, specifying parameters of tasks that evoke differing physiological responses has proved difficult. We have recorded cardiovascular activity while subjects carried out executive and attentional tasks that differed not only psychologically but also in their sensitivity to brain pathology and to pharmacological manipulations. Finapres recordings were made of 30 healthy, normal subjects (mean age 24 years) performing two tasks involving differing aspects of sustained attention and two tasks involving differing aspects of spatial working memory and planning. Measures of heart rate and blood pressure, heart rate and blood pressure variability, and their spectral derivatives revealed differing patterns of cardiovascular adjustment between the "attentional" and "planning" tasks. Each test raised blood pressure, but changes in blood pressure and heart rate variability were confined to the attentional tasks. These findings suggest distinct brain mechanisms subserving different forms of arousal.

Adult↗
PubMed1998

Panic disorder: a theoretical synthesis of medical and psychological approaches.

Panic disorder is a common and disabling condition which frequently leads to excessive reliance upon medical facilities. It is also closely associated with the development of agoraphobia. Medical approaches implicate disturbances of ascending brain noradrenergic and serotonergic systems, and support related pharmacotherapies. Contemporary psychological approaches focus upon misinterpretations of bodily sensations and an undue appreciation of the risk of life-threatening illness, and support cognitive/behavioral psychotherapies. A synthesis is possible by developing the view that the implicated ascending aminergic systems normally play a part in "effortful" or context-sensitive behavior. A relative failure of this under conditions of heightened arousal might be responsible for the rigid patterns of fear, belief, and behavior that characterize these patients. Clinical and research implications are discussed.

Agoraphobia↗
PubMed1995

Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search.

As the catecholamines have long been implicated in attentional processes, the present investigation compared the effects of the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (CLO), the benzodiazepine diazepam (DZP), the D1/D2 antagonist haloperidol (HAL) and a low-tryptophan drink (Lo-TRP) on performance of tests of selective attention with distractors in four groups of young, healthy volunteers. Using a placebo-controlled, cross-over design, selective and dissociable effects on performance were found with each pharmacological manipulation. Specifically, CLO acted to broaden the focus of attention, HAL generally slowed reaction times during attentional search, and DZP and Lo-TRP produced differential effects on stimulus-response compatibility during attentional search. Furthermore, these results underline the usefulness of employing a single test with several neurochemical manipulations, allowing for a comprehensive analysis of the neurochemical basis of attention.

Adult↗
PubMed1995

Contrasting effects of clonidine and diazepam on tests of working memory and planning.

The alpha 2 adrenoceptor has recently been implicated in working memory (WM), a function dependent on the integrity of the prefrontal cortex. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 micrograms/kg and 2.5 micrograms/kg) of the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (CLO) on performance of various computerised tests of WM and planning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Administration of CLO resulted in impulsivity of responding in a planning task, as well as differential dose-dependent effects on two analogous tests of spatial and visual WM. The nature of these effects were suggestive of mnemonic, rather than executive, dysfunction. Conversely, DZP produced specific deficits on tests of spatial WM and planning very similar to those seen following lesions to the frontal lobes. Therefore, these two sedative drugs produce doubly dissociable, dose-dependent effects on different aspects of cognitive function.

Adult↗
PubMed1995

Clonidine and diazepam have differential effects on tests of attention and learning.

The noradrenergic system has repeatedly been implicated in the mediation of attentional processes. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 micrograms/kg and 2.5 micrograms/kg) of the alpha 2 adrenoceptor agonist clonidine (CLO) on performance of various computerised tests of attention and learning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Both doses of CLO were found to impair performance of the RVIP test of sustained attention, while the higher dose alone improved visuo-spatial learning. Conversely, the higher dose of DZP produced profound deficits on visuo-spatial learning, and impaired attentional set-shifting. This study suggests a role for the alpha 2 adrenoceptor in selective attention, and for the benzodiazepine receptor in specific cognitive processes mediated by discrete cortical regions.

Adult↗
PubMed1995

Clinical recovery from panic disorder is associated with evidence of changes in cardiovascular regulation.

Cardiovascular measures (spectral derivatives of heart rate variability, the blood pressure response to standing and plasma noradrenaline levels) have been shown to change as clinical recovery follows the treatment of panic disorder patients with either imipramine or cognitive therapy. These findings can be interpreted as evidence of changes in baroreflex modulation, an important feature of the cardiovascular expression of arousal. This offers further evidence of a dysregulation of arousal in this disorder.

Adolescent↗
PubMed1990

Cardiovascular dystonia in recovered panic patients.

Resting heart rate, heart rate variability and blood pressure; the heart rate and blood pressure response to standing; and the heart rate response to Valsalva's manoeuvre, have been measured in a group of 12 patients with panic disorder and a group of 12 age- and sex-matched normal subjects. The patients had undergone treatment for their panic attacks with cognitive therapy; all had responded and all had been panic-free for a minimum of 4 months (mean 7.6 months). Mood ratings (BDI, BAI and SSAI) were comparable with established norms. The patients nevertheless had a raised resting systolic blood pressure, a reduced resting heart rate and an abnormal orthostatic response.

Adult↗
PubMed1987

Do antidepressants cause postural hypotension by blocking cardiovascular reflexes?

Postural changes in blood pressure, respiratory sinus arrhythmia, the heart rate response to Valsalva's manoeuvre and to standing, and the blood pressure and heart rate responses to isometric exercise have been measured in seven young women taking antidepressant medication and compared with seven controls. Among the patients there was a significant rank order correlation between the degree of postural hypotension and the daily dose of antidepressant medication. There was a significant impairment among the patients of all cardiovascular reflex responses measured, suggesting both cholinergic and adrenergic blockade. These results suggest that postural hypotension associated with antidepressant medication is caused in large part by a failure of reflex peripheral vasoconstriction.

Antidepressive Agents↗
PubMed1983

Postural changes in rib cage and abdominal volume-motion coefficients and their effect on the calibration of a respiratory inductance plethysmograph.

Volume-motion coefficients were determined for the rib cage and abdomen in normal human subjects in upright, supine, and semirecumbent postures by the isovolume calibration technique of Konno and Mead (J Appl Physiol 1967; 22:407-422, using the respiratory inductive plethysmograph (RIP) to measure displacements of rib cage and abdominal walls. Volume motion coefficients changed systematically with posture; those for the rib cage were smallest in the upright posture, and for the abdomen, greatest in the upright posture. These volume motion coefficients were then used to estimate tidal volume during resting breathing in the different postures, and compared with estimates of tidal volume derived from calibration by the change in posture technique reported by Sackner and coworkers (American Review of Respiratory Disease 1980; 122:867-871). Estimates of tidal volume derived from RIP signals using both calibration techniques were compared with independently measured spirometric volume changes. Errors in tidal volume averaged 6% with the isovolume technique and 9 to 23% with the change in posture technique (depending upon whether the calibrating postures were upright, supine or semirecumbent supine). The larger errors with the change in posture calibration method are attributable to both the change in volume motion coefficients with posture and the change in distribution of tidal volume between rib cage and abdomen compartments with change in posture.

Abdomen↗
PubMed1983

Cardiac output, pulmonary hypertension, hypoxaemia and survival in patients with chronic obstructive airways disease.

A prospective study of cor pulmonale in 74 patients relates pulmonary haemodynamics to survival. Mean arterial oxygen tension (PaO2) was 7.2 +/- 0.14 kPa and mean arterial carbon dioxide tension (PaCO2) 6.6 +/- 0.12 kPa at entry. Pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and cardiac output (CO) sitting and supine and where possible on exercise, were measured every one or two years by a floating catheter technique. Survivors showed very little change in pulmonary artery pressure, pulmonary vascular resistance or cardiac output. Those who did not survive, showed a steady increase of PAP and PVR, whether or not they had received continuous oxygen therapy at home. Cardiac output remained normal or slightly elevated despite increasing pulmonary artery pressure. The relationship between VO2 (minute oxygen consumption) and cardiac output remained within the normal or greater than normal range, even on exercise. Although a deteriorating clinical situation may be paralleled by changes in pulmonary haemodynamics, it is questioned whether such changes are causally implicated in mortality.

Cardiac Output↗
PubMed1979

Hypoxaemia in chronic obstructive bronchitis.

Arterial blood gas tensions were studied for six years in 85 patients (59 men, 26 women, mean age 58.8 years) with hypoxaemia associated with chronic bronchitis. All patients who died had a precipitous fall of arterial oxygen tension (PaO2) breathing air. In patients dying within two years of the first appearance of ankle oedema the mean rate of fall of PaO2 was 0.11 kPa/month. Patients who survived two years appeared to deteriorate more slowly (0.017 kPa/month) until some months before death, when they too deteriorated rapidly. Hypoxaemic patients with obstructive airways disease suffer a terminal rapid decline in arterial oxygen tension, which probably indicates real pathological change in the lungs and has important implications for long-term domiciliary oxygen treatment.

Aged↗
PubMed1978

Domiciliary oxygen.

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