Thomas J. Oxley

An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression.

Repetitive transcranial magnetic stimulation (rTMS) is currently undergoing active investigation for use in the treatment of major depression. Recent research has indicated that current methods used to localize the site of stimulation in dorsolateral prefrontal cortex (DLPFC) are significantly inaccurate. However, little information is available on which to base a choice of stimulation site. The aim of the current study was to systematically examine imaging studies in depression to attempt to identify whether there is a pattern of imaging results that suggests an optimal site of stimulation localization. We analysed all imaging studies published prior to 2005 that examined patients with major depression. Studies reporting activation in DLPFC were identified. The DLPFC regions identified in these studies were analysed using the Talairach and Rajkowska-Goldman-Rakic coordinate systems. In addition, we conducted a quantitative meta-analysis of resting studies and studies of serotonin reuptake inhibitor antidepressant treatment. There was considerable heterogeneity in the results between studies. Changes in Brodmann area 9 were relatively consistently identified in resting, cognitive activation and treatment studies included in the meta-analysis. However, there was little consistency in the direction of these changes or the hemisphere in which they were identified. At this stage, the results of imaging studies published to date have limited capacity to inform the choice of optimal prefrontal cortical region for the use in rTMS treatment studies.

An fMRI study of prefrontal brain activation during multiple tasks in patients with major depressive disorder

Objective: Previous research has provided conflicting information regarding the pattern of brain activation associated with cognitive performance in depressed people. We aimed to assess brain activation related to cognitive performance during planning and working memory tasks. Method: fMRI scans were conducted using a modified Tower of London task and a 2‐back task in 13 patients with major depressive disorder and a matched control group. Results: Task performance was impaired in the depressed group on the Tower of London task but there were no differences between the groups in task performance on the n‐back task. The patient group showed widespread increased brain activation in both tasks. There was considerable overlap in increased activation between the two tasks, especially in right prefrontal cortical regions. Conclusions: Patients with depression exhibit increased brain activation, especially in right prefrontal regions, across several types of cognitive task activity. Patients with depression may recruit greater brain regions to achieve similar or even poorer task performance than control subjects. Hum Brain Mapp, 2008.

Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study

BACKGROUND Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. METHODS Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. RESULTS All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. CONCLUSIONS Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.

Repetitive transcranial magnetic stimulation reveals abnormal plastic response to premotor cortex stimulation in schizophrenia.

BACKGROUND Schizophrenia may be characterized by abnormal plastic modulation in cortical neuronal circuits. Activation of premotor cortex using repetitive transcranial magnetic stimulation (rTMS) produces suppression of cortical excitability in primary motor cortex. We hypothesized that premotor rTMS would cause less suppression of motor cortical excitability in patients with schizophrenia than in control subjects. METHODS Twelve patients diagnosed with schizophrenia and twelve healthy control subjects underwent subthreshold rTMS to the premotor area in a 15-min conditioning train. Measurements of primary motor cortical excitability (motor evoked potential; MEP), the resting motor threshold (RMT), and cortical inhibition (CI) were taken before and after the rTMS. RESULTS There was no difference in RMT between groups at baseline, although the patient group had less CI than the control group at baseline. Following rTMS, the change in both MEP size and RMT between groups was significant. After rTMS, MEP size was suppressed in the control group and increased in the patient group, whereas RMT increased in the normal control group and decreased in the patient group. CONCLUSIONS Patients with schizophrenia demonstrate abnormal brain responses to rTMS applied to the premotor cortex that appear to relate to reduced motor cortical inhibition.

Acute Ischemic Stroke Time, Penumbra, and Reperfusion

Current guidelines advocate intravenous thrombolysis for patients with ischemic stroke <4.5 hours from onset without additional imaging beyond noncontrast computed tomography (CT) of the brain.1 Rapid administration of intravenous tissue-type plasminogen activator (IV-tPA) will reduce disability. Treatment of patients within 3 hours has an odds ratio of 1.53 (95% confidence interval, 1.26–1.86) for a favorable outcome (modified Rankin scale [mRS], 0–2) at 3 months.2 However, this represents an absolute increase of 9% compared with placebo and is available to a minority of patients with ischemic stroke because of the rigid time constraints.3 Modern stroke imaging grants unprecedented access to the pathophysiology in individual patients with stroke. Time remains of key importance with respect to patient outcomes. However, it is now possible to not only routinely visualize the causative occlusion, but also estimate the ischemic core, the penumbral tissue at risk if reperfusion does not occur, and the state of the collateral blood supply. The current focus of Acute Ischemic Stroke (AIS) intervention should be to achieve reperfusion of the penumbra. Recent trials point to potential avenues to improve patient access by imaging-based patient selection and the importance of rapid and complete reperfusion of the penumbra. Three parenchymal vascular states exist in varying proportions in each AIS patient. These are the ischemic core, the penumbra, and a region of benign oligemia.4,5 Separating the penumbra from the ischemic core is of critical importance in guiding stroke therapy. So too is separating the penumbra from the region of benign oligemia. By definition, the penumbra is the region of tissue that is at risk of being recruited into the ischemic core. Thus, the penumbra is the principal target for reperfusion and, therefore, should dictate patient selection. Given the progressive nature of ischemic stroke, establishing the continued existence of …

Acute Ischemic Stroke

Current guidelines advocate intravenous thrombolysis for patients with ischemic stroke <4.5 hours from onset without additional imaging beyond noncontrast computed tomography (CT) of the brain.1 Rapid administration of intravenous tissue-type plasminogen activator (IV-tPA) will reduce disability. Treatment of patients within 3 hours has an odds ratio of 1.53 (95% confidence interval, 1.26–1.86) for a favorable outcome (modified Rankin scale [mRS], 0–2) at 3 months.2 However, this represents an absolute increase of 9% compared with placebo and is available to a minority of patients with ischemic stroke because of the rigid time constraints.3 Modern stroke imaging grants unprecedented access to the pathophysiology in individual patients with stroke. Time remains of key importance with respect to patient outcomes. However, it is now possible to not only routinely visualize the causative occlusion, but also estimate the ischemic core, the penumbral tissue at risk if reperfusion does not occur, and the state of the collateral blood supply. The current focus of Acute Ischemic Stroke (AIS) intervention should be to achieve reperfusion of the penumbra. Recent trials point to potential avenues to improve patient access by imaging-based patient selection and the importance of rapid and complete reperfusion of the penumbra. Three parenchymal vascular states exist in varying proportions in each AIS patient. These are the ischemic core, the penumbra, and a region of benign oligemia.4,5 Separating the penumbra from the ischemic core is of critical importance in guiding stroke therapy. So too is separating the penumbra from the region of benign oligemia. By definition, the penumbra is the region of tissue that is at risk of being recruited into the ischemic core. Thus, the penumbra is the principal target for reperfusion and, therefore, should dictate patient selection. Given the progressive nature of ischemic stroke, establishing the continued existence of …

A transcranial magnetic stimulation study of abnormal cortical inhibition in schizophrenia

Previous research suggests that patients with schizophrenia demonstrate deficits in a range of parameters of motor cortical and cognitive inhibition. I-wave facilitation and long-interval cortical inhibition (LICI) are two paired pulse transcranial magnetic stimulation paradigms that appear to assess aspects of cortical inhibitory function that have not previously been assessed in this patient group. Eighteen patients with schizophrenia (nine medication-free) were compared with eight control subjects. We assessed resting motor threshold (RMT) levels, LICI and I-wave facilitation. RMT levels did not differ between the three groups. There was a significant overall difference in I-wave facilitation levels. Both patient groups as compared with the control group showed increased facilitation. There were no differences between the groups in the measure of LICI. Patients with schizophrenia appear to have increased I-wave facilitation. Increased I-wave facilitation suggests deficient function of cortical inhibitory GABAergic activity. This is consistent with previous research that has found deficient cortical inhibition in patients with schizophrenia.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

A study of the effects of lorazepam and dextromethorphan on the response to cortical 1 Hz repetitive transcranial magnetic stimulation.

We studied the effects of lorazepam and dextromethorphan on the responses to 1 Hz repetitive transcranial magnetic stimulation applied to the left human motor cortex. Lorazepam, dextromethorphan or placebo was administered to 45 normal controls in a double-blind fashion 2.5 h before the repetitive transcranial magnetic stimulation procedure. Motor cortical excitability was measured with single transcranial magnetic stimulation pulses before and after 15 min of 1 Hz repetitive transcranial magnetic stimulation applied at supra-threshold intensity. 1 Hz repetitive transcranial magnetic stimulation resulted in a decrease in motor cortical excitability in the placebo group but not in the groups taking lorazepam or dextromethorphan. These results suggest that cortical responses to 1 Hz repetitive transcranial magnetic stimulation are dependent on activity at both &ggr;-aminobutyric acid and N-methyl-D-asparate receptor systems.

Antiplatelet Resistance and Thromboembolic Complications in Neurointerventional Procedures

Antiplatelet resistance is emerging as a significant factor in effective secondary stroke prevention. Prevalence of aspirin and clopidogrel resistance is dependent upon laboratory test and remains contentious. Large studies in cardiovascular disease populations have demonstrated worse ischemic outcomes in patients with antiplatelet resistance, particularly in patients with coronary stents. Thromboembolism is a complication of neurointerventional procedures that leads to stroke. Stroke rates related to aneurysm coiling range from 2 to 10% and may be higher when considering silent ischemia. Stroke associated with carotid stenting is a major cause of morbidity. Antiplatelet use in the periprocedure setting varies among different centers. No guidelines exist for use of antiplatelet regimens in neurointerventional procedures. Incidence of stroke in patients post procedure may be partly explained by resistance to antiplatelet agents. Further research is required to establish the incidence of stroke in patients with antiplatelet resistance undergoing neurointerventional procedures.