Aziz M. Uluğ

Differential patterns of striatal activation in young children with and without ADHD

BACKGROUND Cognitive control, defined as the ability to suppress inappropriate thoughts and actions, is compromised in attention-deficit/hyperactivity disorder (ADHD). This study examines the neural basis of this deficit. METHODS We used a paradigm that incorporates a parametric manipulation within a go/nogo task, so that the number of go trials preceding a nogo trial is varied to tax the neural systems underlying cognitive control with increasing levels of interference. RESULTS Using this paradigm in combination with event-related functional magnetic resonance imaging (fMRI), we show that children without ADHD have increased susceptibility to interference with increasing numbers of go trials preceding a nogo trial, but children with ADHD have difficulty even with a single go trial preceding a nogo trial. In addition, children with ADHD do not activate frontostriatal regions in the same manner as normally developing children, but rather rely on a more diffuse network of regions, including more posterior and dorsolateral prefrontal regions. CONCLUSIONS Normal immature cognition may be characterized as being susceptible to interference and supported by the maturation of frontostriatal circuitry. ADHD children show a slightly different cognitive profile at 6 to 10 years of age that is paralleled by a relative lack of or delay in the maturation of ventral frontostriatal circuitry.

Quantitative assessment of blood flow, blood volume and blood oxygenation effects in functional magnetic resonance imaging

The ability to measure the effects of local alterations in blood flow, blood volume and oxygenation by nuclear magnetic resonance has stimulated a surge of activity in functional MRI of many organs, particularly in its application to cognitive neuroscience. However, the exact description of these effects in terms of the interrelations between the MRI signal changes and the basic physiological parameters has remained an elusive goal. We here present this fundamental theory for spin-echo signal changes in perfused tissue and validate it in vivo in the cat brain by using the physiological alteration of hypoxic hypoxia. These experiments show that high-resolution absolute blood volume images can be obtained by using hemoglobin as a natural intravascular contrast agent. The theory also correctly predicts the magnitude of spin-echo MRI signal intensity changes on brain activation and thereby provides a sound physiological basis for these types of studies.

A neural basis for the development of inhibitory control

The present study explores the neural basis of the development of inhibitory control by combining functional neuroimaging with a parametric manipulation of a go-nogo paradigm. We demonstrate how the maturation of ventral fronto-striatal circuitry underlies the development of this ability. We used event-related fMRI to examine the effect of interference on neural processes involved in inhibitory control in children and adults. Nogo trials were preceded by either 1, 3 or 5 go trials and then compared to one another. Both children and adults showed an increase in errors with increasing interference. Successful response inhibition was associated with stronger activation of prefrontal and parietal regions for children than for adults. In adults, activation in ventral prefrontal regions increased with increasing interference from go trials. Unlike adults, the circuitry appeared to be maximally activated in children when suppressing a behavioral response regardless of the number of preceding responses. Furthermore, activation in ventral fronto-striatal regions correlated with both age and performance. These findings suggest that immature cognition is more susceptible to interference and this is paralleled by maturational differences in underlying fronto-striatal circuitry.

Cerebellothalamocortical connectivity regulates penetrance in dystonia.

Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance diffusion tensor imaging and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebellothalamocortical fiber tracts, likely developmental in origin, in both manifesting and clinically nonmanifesting dystonia mutation carriers. In these subjects, reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamocortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.

Parametric manipulation of conflict and response competition using rapid mixed-trial event-related fMRI

In the current study we examined the influence of preceding context on attentional conflict and response competition using a flanker paradigm. Nine healthy right-handed adults participated in a rapid mixed trial event-related functional magnetic resonance imaging (fMRI) study, in which increasing numbers of either compatible or incompatible trials preceded an incompatible trial. Behaviorally, reaction times on incompatible trials increased as a function of the number of preceding compatible trials. Several brain regions showed monotonic changes to the preceding context manipulation. The most common pattern was observed in anterior cingulate, dorsolateral prefrontal, and superior parietal regions. These areas showed an increase in activity for incompatible trials as the number of preceding compatible trials increased and a decrease in activity for incompatible trials as the number of preceding incompatible trials increased. Post hoc analysis showed that while the MR signal in the anterior cingulate and dorsolateral prefrontal regions peaked before the superior parietal region, the dorsolateral prefrontal MR signal peaked early and remained at this level. These findings are consistent with the conflict monitoring theory that postulates that the anterior cingulate cortex detects or monitors conflict, while PFC is involved in control adjustments that may then lead to modulation of superior parietal cortex in top-down biasing of attention.

Quantitative objective markers for upper and lower motor neuron dysfunction in ALS

Objective: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. Methods: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging (1H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. Results: 1H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale–Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. Conclusions: 1H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

Orientation-independent diffusion imaging without tensor diagonalization: anisotropy definitions based on physical attributes of the diffusion ellipsoid.

Diffusion tensor imaging can provide a complete description of the diffusion process in tissue. However, this description is not unique but is orientation dependent, and, to quantify properly the intrinsic orientation‐independent diffusion properties of the tissue, a set of three rotationally invariant quantities is needed. Instead of using the tensor eigenvalues for this, we define a new set consisting of scaled invariants that have the proper magnitude of actual diffusion constants and that are directly related to the physical attributes of the diffusion ellipsoid, namely, its average radius, surface, and volume. Using these three physical invariants, a new family of anisotropy measures is defined that are normalized between zero (isotropic) and one (completely anisotropic). Because rotational invariants are used, this approach does not require tensor diagonalization and eigenvalue determination and is therefore not susceptible to potential artifacts induced during these number manipulations. The relationship between the new anisotropy definitions and existing orientation‐independent anisotropy indices obtained from eigenvalues is discussed, after which the new approach is evaluated for a group of healthy volunteers. J. Magn. Reson. Imaging 1999;9:804–813.

Diffusion Tensor Imaging and Tractography of Median Nerve: Normative Diffusion Values

OBJECTIVE The purposes of this study were to visualize the human median nerve on diffusion tensor imaging and to determine the normal fractional anisotropy (FA) value and apparent diffusion coefficient (ADC) of the normal median nerve. SUBJECTS AND METHODS The wrists of 20 healthy volunteers and of two patients with carpel tunnel syndrome were examined with a 3-T MRI system with a standard eight-channel sensitivity-encoding head coil. Diffusion tensor imaging was performed with a spin-echo echo-planar sequence. A T1-weighted sequence was performed for anatomic reference. After tractography, the FA value and ADC of the whole nerve were calculated automatically. Manual focal measurements also were obtained at the levels of the flexor retinaculum, wrist, and forearm. RESULTS We visualized the median nerve with MR diffusion tensor tractography and followed the nerve for approximately 77.5 mm. We found the normative diffusion values of the median nerve were an FA of 0.709 +/- 0.046 (SD) and an ADC of 1.016 +/- 0.129 x 10(-3) mm2/s. There was a statistically significant difference between the FA values obtained at the level of the flexor retinaculum and the values obtained from the other parts of the median nerve (p < 0.0001). We found a decrease in FA value (p < 0.01) and an increase in ADC (p < 0.05) with advancing age. CONCLUSION The normative diffusion values of the human median nerve can be used as a reference in evaluation, diagnosis, and follow-up of entrapment, trauma, and regeneration of the median nerve.

Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy

BackgroundThe phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. Multislice proton MRS imaging (MRSI) has previously detected more extensive brain abnormalities in X-ALD than conventional MRI, which has been suggested to predict impending demyelination. However, the significance of these changes is unclear. ObjectiveThe purpose of this study was to determine the long-term sensitivity and specificity of MRSI for disease progression in X-ALD. MethodsTwenty-five patients with X-ALD were investigated (average age, 15 years; range, 2–43 years) with MRI and proton MRSI at baseline and follow-up MRI over a mean period of 3.5 years. Eight patients had normal MRI findings at baseline and on follow-up (noncerebral group), 11 had abnormal MRI at baseline and no change on follow-up (cerebral nonprogressive group), and 6 had progressive MRI abnormalities (cerebral progressive group). On MRSI, voxels were analyzed in the normal MRI–appearing perilesional white matter, or in the corresponding area in the noncerebral group. ResultsThe concentration ratio of N-acetylaspartate (NAA) to choline was the most sensitive indicator of disease progression. The average NAA/choline ratio was 5.99 for the noncerebral group, 5.75 for the cerebral nonprogressive group, and 3.74 for the cerebral progressive group (p = 0.002). At a cut-off point of 5.0, the NAA/choline ratio predicted disease progression in all patients with six cerebral progressive disease (sensitivity 100%). The specificity was 83%, the positive predictive value was 66%, and the negative predictive value was 100%. ConclusionsMultislice proton MRS imaging is able to identify impending or beginning degeneration in white matter that still appears normal on conventional MRI. Multislice proton MRSI may be a suitable technique for the prediction of lesion progression on MRI in X-linked adrenoleukodystrophy.

Distribution of microstructural damage in the brains of professional boxers: A diffusion MRI study

To investigate and localize cerebral abnormalities in professional boxers with no history of moderate or severe head trauma.