Michael Krams

The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans.

Autism is a biological disorder which affects social cognition, and understanding brain abnormalities of the former will elucidate the brain basis of the latter. We report structural MRI data on 15 high-functioning individuals with autistic disorder. A voxel-based whole brain analysis identified grey matter differences in an amygdala centered system relative to 15 age- and IQ-matched controls. Decreases of grey matter were found in anterior parts of this system (right paracingulate sulcus, left inferior frontal gyrus). Increases were found in posterior parts (amygdala/peri-amygdaloid cortex, middle temporal gyrus, inferior temporal gyrus), and in regions of the cerebellum. These structures are implicated in social cognition by animal, imaging and histopathological studies. This study therefore provides converging evidence of the physiological basis of social cognition.

The time course of changes during motor sequence learning: a whole-brain fMRI study.

There is a discrepancy between the results of imaging studies in which subjects learn motor sequences. Some experiments have shown decreases in the activation of some areas as learning increased, whereas others have reported learning-related increases as learning progressed. We have exploited fMRI to measure changes in blood oxygen leve-dependent (BOLD) signal throughout the course of learning. T2*-weighted echo-planar images were acquired over the whole brain for 40 min while the subjects learned a sequence eight moves long by trial and error. The movements were visually paced every 3.2 s and visual feedback was provided to the subjects. A baseline period followed each activation period. The effect due to the experimental conditions was modeled using a square-wave function, time locked to their occurrence. Changes over time in the difference between activation and baseline signal were modeled using a set of polynomial basis functions. This allowed us to take into account linear as well as nonlinear changes over time. Low-frequency changes over time common to both activation and baseline conditions (and thus not learning related) were modeled and removed. Linear and nonlinear changes of BOLD signal over time were found in prefrontal, premotor, and parietal cortex and in neostriatal and cerebellar areas. Single-unit recordings in nonhuman primates during the learning of motor tasks have clearly shown increased activity early in learning, followed by a decrease as learning progressed. Both phenomena can be observed at the population level in the present study.

An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, −12.3 to −4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

The Attentional Role of the Left Parietal Cortex: The Distinct Lateralization and Localization of Motor Attention in the Human Brain

It is widely agreed that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. It is thought that the visuospatial orienting role of the right parietal lobe is related to its role in the production of overt eye movements. The experiments reported here test the possibility that other parietal regions may be important for directing attention in relation to response modalities other than eye movement. Specifically, we used positron emission tomography (PET) to test the hypothesis that a left parietal area, the supramarginal gyrus, is important for attention in relation to limb movements (Rushworth et al., 1997; Rushworth, Ellison, & Walsh, in press). We have referred to this process as motor attention to distinguish it from orienting attention. In one condition subjects spent most of the scanning period covertly attending to left hand movements that they were about to make. Activity in this first condition was compared with a second condition with identical stimuli and movement responses but lacking motor attention periods. Comparison of the conditions revealed that motor attention related activity was almost exclusively restricted to the left hemisphere despite the fact that subjects only ever made ipsilateral, left-hand responses. Left parietal activity was prominent in this comparison, within the parietal lobe the critical region for motor attention was the supramarginal gyrus and the adjacent anterior intraparietal sulcus (AIP), a region anterior to the posterior parietal cortex identified with orienting attention. In a second part of the experiment we compared a condition in which subjects covertly rehearsed verbal responses with a condition in which they made verbal responses immediately without rehearsal. A comparison of the two conditions revealed verbal rehearsal-related activity in several anterior left hemisphere areas including Brocas area. The lack of verbal rehearsal-related activity in the left supra-marginal gyrus confirms that this area plays a direct role in motor attention that cannot be attributed to any strategy of verbal mediation. The results also provide evidence concerning the importance of ventral premotor (PMv) and Brocas area in motor attention and language processes.

Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): An Adaptive Dose-Response Study of UK-279,276 in Acute Ischemic Stroke

Background and Purpose— UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response–finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. Methods— A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (&Dgr;SSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. Results— Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean &Dgr;SSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on &Dgr;SSS in the tissue plasminogen activator–treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections. Conclusions— UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.

A Functional Anatomy of Anticipatory Anxiety

Anticipatory anxiety is a complex combination of a future-oriented cognitive state, negative affect, and autonomic arousal. A dual-task paradigm of anticipation of electric shocks and a motor-learning task was used to examine the changes in neural patterns of activation associated with modulation of the cognitive state in anxiety by a distracting motor task. We used positron emission tomography (PET) and 15O-water to measure regional cerebral blood flow (rcbf) in 10 healthy male volunteers. A 2x2 factorial design-(shock vs no shock) x (low vs high distraction) was used with three scans per condition. Twelve PET scans were performed on each subject. In six of these scans, subjects were given electric shocks. In all scans, subjects also simultaneously performed a motor repetition (low distraction) or learning (high distraction) task. Galvanic skin conductance (GSR), Spielberger State and Trait Anxiety Inventory (STAI), and self-report data were also collected. In comparisons between the shock and no-shock conditions, the main finding was of increased rcbf in the left insula (-38,8,8) (z = 4.85, P<0.05 corrected) and a homologous area in the right insula at a lower threshold (z =3.20, P = 0.001 uncorrected). Other areas activated were the right superior temporal sulcus, left fusiform, and left anterior cingulate. Using the STAI-state scores as a covariate of interest, significant correlations with rCBF were seen in the left orbitofrontal cortex, left insula, and left anterior cingulate cortex. There was no significant distraction effect as measured by the STAI, self-report, GSR response or interactional analysis of the PET data. These findings support the role of paralimbic structures as neural substrates of anticipatory anxiety. The failure to demonstrate behavioral and neurophysiological changes with the distractor task may reflect the modest increases in anxiety with the shock, the relatively simple distractor task, and small sample size.

Adaptive designs in clinical drug development--an Executive Summary of the PhRMA Working Group.

A PhRMA Working Group on adaptive clinical trial designs has been formed to investigate and facilitate opportunities for wider acceptance and usage of adaptive designs and related methodologies. A White Paper summarizing the findings of the group is in preparation; this article is an Executive Summary for that full White Paper, and summarizes the findings and recommendations of the group. Logistic, operational, procedural, and statistical challenges associated with adaptive designs are addressed. Three particular areas where it is felt that adaptive designs can be utilized beneficially are discussed: dose finding, seamless Phase II/III trials designs, and sample size reestimation.

Innovative Approaches for Designing and Analyzing Adaptive Dose-Ranging Trials

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.

Adaptive Bayesian Designs for Dose-Ranging Drug Trials

In the standard type of phase II efficacy trial, patients are assigned to a dose from among those being considered (usually 4 to 12 in number). Assignment is random, usually with equal numbers of patients assigned to each dose. Based on the results of the trial, a decision is made to either enter phase III in the drug’s development, stop the drug’s development, or conduct another phase II trial. Such a design is inefficient, in terms of both time and resources. We have developed an innovative class of designs that we are introducing into practice. In this case study we describe the designs, address difficulties in implementing them in actual clinical trials, and relay our experience with using them.

Kallmann’s syndrome Mirror movements associated with bilateral corticospinal tract hypertrophy

Objective: To investigate the etiology of mirror movements in patients with X-linked Kallmann’s syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. Background: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. Methods: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann’s syndrome (aKS) and nine age-matched normal (healthy) men. Results: Hypertrophy of the corpus callosum was found in both Kallmann’s syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. Conclusion: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.