Tim Donovan

Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates

Objective To investigate the effect of hyperventilation on cerebral blood flow in traumatic brain injury. Design A prospective interventional study. Setting A specialist neurocritical care unit. Patients Fourteen healthy volunteers and 33 patients within 7 days of closed head injury. Interventions All subjects underwent positron emission tomography imaging of cerebral blood flow. In patients, Paco2 was reduced from 36 ± 1 to 29 ± 1 torr (4.8 ± 0.1 to 3.9 ± 0.1 kPa) and measurements repeated. Jugular venous saturation (Sjvo2) and arteriovenous oxygen content differences (AVDO2) were monitored in 25 patients and values related to positron emission tomography variables. Measurements and Main Results The volumes of critically hypoperfused and hyperperfused brain (HypoBV and HyperBV, in milliliters) were calculated based on thresholds of 10 and 55 mL·100g−1·min−1, respectively. Whereas baseline HypoBV was significantly higher in patients (p < .05), baseline HyperBV was similar to values in healthy volunteers. Hyperventilation resulted in increases in cerebral perfusion pressure (p < .0001) and reductions in intracranial pressure (p < .001), whereas Sjvo2 (>50%) and AVDO2 (<9 mL/mL) did not exceed global ischemic thresholds. However, despite these beneficial effects, hyperventilation shifted the cerebral blood flow distribution curve toward the hypoperfused range, with a decrease in global cerebral blood flow (31 ± 1 to 23 ± 1 mL·100g−1·min−1;p < .0001) and an increase in HypoBV (22 [1–141] to 51 [2–428] mL;p < .0001). Hyperventilation-induced increases in HypoBV were apparently nonlinear, with a threshold value between 34 and 38 torr (4.5–5 kPa). Conclusions Hyperventilation increases the volume of severely hypoperfused tissue within the injured brain, despite improvements in cerebral perfusion pressure and intracranial pressure. Significant hyperperfusion is uncommon, even at a time when conventional clinical management includes a role for modest hyperventilation. These reductions in regional cerebral perfusion are not associated with ischemia, as defined by global monitors of oxygenation, but may represent regions of potentially ischemic brain tissue.

Diffusion tensor imaging of brain tumours at 3 T: a potential tool for assessing white matter tract invasion?

AIM To determine whether diffusion tensor imaging (DTI) of brain tumours can demonstrate abnormalities distal to hyperintensities on T2-weighted images, and possibly relate these to tumour grade. MATERIALS AND METHODS Twenty patients with histologically confirmed supratentorial tumours, both gliomas (high and low grade) and metastases, were imaged at 3T using T2-weighted and DTI sequences. Regions of interest (ROI) were drawn within the tumour, in white matter at various distances from the tumour and in areas of abnormality on DTI that appeared normal on T2-weighted images. The relative anisotropy index (RAI)-a measure of white matter organization, was calculated for these ROI. RESULTS The abnormality on DTI was larger than that seen on T2-weighted images in 10/13 patients (77%) with high-grade gliomas. New abnormalities were seen in the contralateral white matter in 4/13 (30%) of these cases. In these high-grade tumours the RAI in areas of white matter disruption with normal appearance on T2-weighted images was reduced (0.19+/-0.04). Even excluding patients with previous radiotherapy this difference remains significant. In all non high-grade tumours (WHO grade II gliomas and metastases) the tumour extent on DTI was identical to the abnormalities shown on T2-weighted imaging and RAI measurements were not reduced (0.3+/-0.04). CONCLUSIONS Subtle white matter disruption can be identified using DTI in patients with high-grade gliomas. Such disruption is not identified in association with metastases or low-grade gliomas despite these tumours producing significant mass effect and oedema. We suggest the changes in DTI may be due to tumour infiltration and that the DTI may provide a useful method of detecting occult white matter invasion by gliomas.

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory

Learning depends on surprise and is not engendered by predictable occurrences. In this functional magnetic resonance imaging (fMRI) study of causal associative learning, we show that dorsolateral prefrontal cortex (DLPFC) is associated specifically with the adjustment of inferential learning on the basis of unpredictability. At the outset, when all associations were unpredictable, DLPFC activation was maximal. This response attenuated with learning but, subsequently, activation here was evoked by surprise violations of the learned association. Furthermore, the magnitude of DLPFC response to a surprise event was sensitive to the relationship that had been learned and was predictive of subsequent behavioral change. In short, the physiological response properties of right DLPFC satisfied specific predictions made by associative learning theory.

Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values

Regional cerebral blood flow (CBF) was studied with O15-water positron emission tomography and anatomic region-of-interest analysis on coregistered magnetic resonance in patients with idiopathic (n = 12) and secondary (n = 5) normal pressure hydrocephalus (NPH). Mean CBF was compared with values obtained from healthy volunteers (n = 12) and with clinical parameters. Mean CBF was significantly decreased in the cerebrum and cerebellum of patients with NPH. The regional analysis demonstrated that CBF was reduced in the basal ganglia and the thalamus but not in white matter regions. The results suggest that the role of the basal ganglia and thalamus in NPH may be more prominent than currently appreciated. The implications for theories regarding the pathogenesis of NPH are discussed.

Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study.

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamines effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

The diagnosis of lameness associated with distal limbpathology in a horse: A comparison of radiography, computed tomography and magnetic resonance imaging

A cadaver limb from an eight-year-old horse with right forelimb lameness that was relieved with an intra-articular distal interphalangeal joint block was imaged with radiographs, spiral computed tomography (CT) and magnetic resonance imaging (MRI). Spiral CT demonstrated several lucencies within the deep digital flexor tendon immediately proximal to the navicular bone. On MRI these areas had increased signal and there was enlargement of the tendon at this site. Effusion in the proximal interphalangeal joint and navicular bursa and thinning of the fibrocartilage of the navicular bone were also observed on MRI images. These changes were not detected on radiographs. Histopathology confirmed that there were focal areas of collagen necrosis within the deep digital flexor tendon with thinning and degenerative changes in the fibrocartilage of the navicular bone.

Regional brain activations predicting subsequent memory success: an event-related fMRI study of the influence of encoding tasks.

We determined the brain regions that were differentially sensitive to two, randomly inter-mixed tasks: Deep Encoding, in which subjects processed items according to their meaning (is the word pleasant or unpleasant?) and Shallow Encoding, in which items were processed according to two underlined letters in the word (are the letters in alphabetical order?). The former task was associated with activations in a set of brain regions including left lateral prefrontal cortex (PFC) and left medial temporal cortex. The latter showed relatively greater activation in right PFC. Both findings are consistent with predictions made on the basis of previous functional neuroimaging work. Following scanning, each subject underwent a recognition memory task. The results of these provided the basis for a further sub-division of encoding events, according to whether they were predictive of subsequent recognition success or not. Unsurprisingly, recognition performance was greater for words that had been deeply encoded. For both encoding conditions, words that were subsequently recognised were associated with greater activation in a sub-set of regions identified by the deep versus shallow contrast. These included left PFC and medial temporal regions. In left PFC this performance-predicting activation was significantly greater for the deep encoding condition. Our results support previous studies suggesting a role for left PFC and medial temporal cortex in episodic memory encoding. They provide more evidence, too, for a less consistent finding: the interaction between the encoding task and the success of subsequent recognition.

Cerebrovascular pressure reactivity is related to global cerebral oxygen metabolism after head injury

Background: After head injury, impaired cerebrovascular autoregulation has been associated with abnormally high or low cerebral blood flow. The physiological relevance of cerebral blood flow levels is difficult to assess in these patients, whose cerebral metabolic rate for oxygen (CMRo2) is known to be abnormal. Investigation of these relations requires quantitative measures of cerebral blood flow and CMRO2, to allow assessment of oxygen supply and demand relations. Objectives: To investigate the relation between dysautoregulation and global cerebral oxygen metabolism following head injury. Methods: Using positron emission tomography, global cerebral blood flow, CMRo2, and oxygen extraction fraction were determined in 22 patients who were investigated in 26 examinations on days 1 to 11 (mean (SD), 3.5 (2.3)) after head injury. Cerebrovascular pressure reactivity was assessed using a pressure reactivity index, calculated as the moving linear correlation coefficient between mean arterial blood pressure and intracranial pressure. Outcome was assessed six months after injury using the Glasgow outcome scale. Results: Low CMRo2 was associated with disturbed pressure reactivity (inverse function, R2 = 0.21, p = 0.018) and there was a correlation between disturbed pressure reactivity and oxygen extraction fraction (quadratic function, R2 = 0.55, p = 0.0001). There was no significant relation between pressure reactivity and cerebral blood flow. An unfavourable outcome was associated with disturbed pressure reactivity. There was no significant relation between outcome and CMRo2 or oxygen extraction fraction. Conclusions: There is a close relation between dysautoregulation and abnormal cerebral metabolism but not blood flow. Further studies are needed to determine whether metabolic dysfunction is a result of or a cause of disturbed pressure reactivity, and to establish if there is a relation between cerebral oxygen metabolism and outcome.

Cerebral autoregulation among patients with symptoms of hydrocephalus

OBJECTIVE To study the relationship between the resistance to cerebrospinal fluid (CSF) outflow and cerebral autoregulation. METHODS We examined 35 patients who presented with ventricular dilation and clinical symptoms of communicating hydrocephalus. For all of these patients, CSF compensatory reserve was investigated by using a computerized infusion test, with simultaneous recording of blood flow velocity wave forms (by using transcranial Doppler ultrasonography) and arterial blood pressure (with a Finapress finger cuff). The resistance to CSF outflow was calculated as the absolute increase in intracranial pressure (interpolated over vasogenic waves) divided by the infusion rate (1.5 ml/min in most cases). The index of autoregulation was assessed as a correlation coefficient (moving time window of 5 min) between slow waves (with periods of 20 s to 2 min) in mean blood flow velocity and cerebral perfusion pressure. RESULTS The mean intracranial pressure increased during the test, from 6 mm Hg (standard deviation, 6 mm Hg) to 20 mm Hg (standard deviation, 10 mm Hg) (P < 0.0001). The index of autoregulation was significantly correlated with the resistance to CSF outflow (r = −0.41, P < 0.03), indicating better autoregulation with greater resistance to CSF outflow. CONCLUSION Patients presenting with ventricular dilation may exhibit either decreased (atrophy) or increased (normal-pressure hydrocephalus) resistance to CSF outflow. Increased resistance is correlated with preserved autoregulation. Patients with low resistance, suggesting brain atrophy, more often have disturbed autoregulation in the middle cerebral artery territory, as assessed by transcranial Doppler ultrasonography.

The sacroiliac joints: evaluation using nuclear scintigraphy. Part 1: The normal horse

REASONS FOR PERFORMING STUDY Sacroiliac (SI) disease is recognised as a cause of poor hindlimb action but differential diagnosis is often difficult. HYPOTHESES That in clinically normal horses there would be a significant difference in the ratio of radiopharmaceutical uptake (RU) between the fifth lumbar vertebra (L5) and each tuber sacrale (TS) and between L5 and each SI joint; and that these ratios would alter with age, but ratios would be bilaterally symmetrical. METHODS Dorsal scintigraphic images of the SI region of 15 horses, selected randomly from the clinic database, were analysed by 2 of the authors, comparing noncorrected and motion-corrected images. To determine scintigraphic anatomy, the scintigraphic images of 10 Thoroughbred horses were superimposed over a ventrodorsal radiographic image of an isolated pelvis. Dorsal scintigraphic images of 40 clinically normal horses age 3-16 years were evaluated using subjective examination, profile analysis and quantification using regions of interest. RESULTS The tubera sacrale were seen as 2 well-defined oval regions immediately to the left and right of the midline, abaxial to which were larger, approximately oval areas with less RU, representing uptake in the SI joints. The definition between the SI region and the TS was more obvious in younger horses. Nonmotion-corrected images were often not of diagnostic quality or could be misinterpreted as abnormal. There were significant differences in RU between the TS and SI joints compared to L5, and decreased RU in the tubera sacrale with increasing age, but no change of uptake in the SI joint region and no effect of gender on RU. There was a high degree of left-right symmetry of the TS and SI joint regions. CONCLUSIONS AND POTENTIAL RELEVANCE The scintigraphic images of horses with suspected sacroiliac joint disease should be compared with images of normal horses of comparable age. In normal horses, there was a high degree of symmetry; therefore, marked left-right asymmetry is likely to be abnormal.