Craig A. Branch

Diffusion-Tensor Imaging Implicates Prefrontal Axonal Injury in Executive Function Impairment Following Very Mild Traumatic Brain Injury

PURPOSE To determine whether frontal white matter diffusion abnormalities can help predict acute executive function impairment after mild traumatic brain injury (mTBI). MATERIALS AND METHODS This study had institutional review board approval, included written informed consent, and complied with HIPAA. Diffusion-tensor imaging and standardized neuropsychologic assessments were performed in 20 patients with mTBI within 2 weeks of injury and 20 matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) images (imaging parameters: 3.0 T, 25 directions, b = 1000 sec/mm(2)) were compared by using whole-brain voxelwise analysis. Spearman correlation analyses were performed to evaluate associations between diffusion measures and executive function. RESULTS Multiple clusters of lower frontal white matter FA, including the dorsolateral prefrontal cortex (DLPFC), were present in patients (P < .005), with several clusters also demonstrating higher MD (P < .005). Patients performed worse on tests of executive function. Lower DLPFC FA was significantly correlated with worse executive function performance in patients (P < .05). CONCLUSION Impaired executive function following mTBI is associated with axonal injury involving the DLPFC.

Multifocal White Matter Ultrastructural Abnormalities in Mild Traumatic Brain Injury with Cognitive Disability: A Voxel-Wise Analysis of Diffusion Tensor Imaging

The purpose of the present study is to identify otherwise occult white matter abnormalities in patients suffering persistent cognitive impairment due to mild traumatic brain injury (TBI). The study had Institutional Review Board (IRB) approval, included informed consent and complied with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996. We retrospectively analyzed diffusion tensor MRI (DTI) of 17 patients (nine women, eight men; age range 26-70 years) who had cognitive impairment due to mild TBI that occurred 8 months to 3 years prior to imaging. Comparison was made to 10 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) images derived from DTI (1.5 T; 25 directions; b = 1000) were compared using whole brain histogram and voxel-wise analyses. Histograms of white matter FA show an overall shift toward lower FA in patients. Areas of significantly decreased FA (p < 0.005) were found in the subject group in corpus callosum, subcortical white matter, and internal capsules bilaterally. Co-located elevation of mean diffusivity (MD) was found in the patients within each region. Similar, though less extensive, findings were demonstrated in each individual patient. Multiple foci of low white matter FA and high MD are present in cognitively impaired mild TBI patients, with a distribution that conforms to that of diffuse axonal injury. Evaluation of single subjects also reveals foci of low FA, suggesting that DTI may ultimately be useful for clinical evaluation of individual patients.

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease

The cerebral deposition of amyloid β‐peptide, a central event in Alzheimers disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high‐field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1) transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of β‐amyloid in several brain regions, starting from 10 weeks of age; 2) transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Aβ‐peptide without β‐amyloid deposition; and 3) nontransgenic (NTg) littermates as controls. The transverse relaxation time T2, an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS‐APP mice compared to NTg. No differences in T1 values or proton density were detected between any groups of mice. These results indicate that T2 may be a sensitive marker of abnormalities in this transgenic mouse model of AD. Magn Reson Med 51:794–798, 2004.

The relationship of intracranial venous pressure to hydrocephalus

Little is known about intracranial venous pressure in hydrocephalus. Recently, we reported that naturally occurring hydrocephalus in Beagle dogs was associated with an elevation in cortical venous pressure. We proposed that the normal pathway for cerebrospinal fluid (CSF) absorption includes transcapillary or transvenular absorption of CSF from the interstitial space and that the increase in cortical venous pressure is an initial event resulting in decreased absorption and subsequent hydrocephalus. Further analysis, however, suggests that increased cortical venous pressure reflects the effect of the failure of transvillus absorption with increase in CSF pressure on the venous pressure gradient between ventricle and cortex. Normally, the cortical venous pressure is maintained above CSF pressure by the Starling resistor effect of the lateral lacunae. A similar mechanism is absent in the deep venous system, and thus the pressure in the deep veins is similar to that in the dural sinuses. Decreased CSF absorption causes an increase in CSF pressure followed by an increase in cortical venous pressure without a similar increase in periventricular venous pressure. The periventricular CSF to venous (transparenchymal) pressure (TPP) gradient increases. In contrast, cortical vein pressure remains greater than CSF pressure (negative TPP). The elevated periventricular TPP gradient causes ventricular dilatation and decreased periventricular cerebral blood flow (CBF), a condition that persists even if the CSF pressure returns to normal, particularly if tissue elastance is lessened by tissue damage. If deep CBF is to be maintained, periventricular venous pressure must increase. Since the veins are in a continuum, cortical venous pressure will further increase above the CSF pressure. Understanding these principles related to intracranial venous pressure helps in the selection of shunt characteristics that best match the pathologic condition.

Early detection of schizophrenia by diffusion weighted imaging.

A novel magnetic resonance imaging method was used to determine whether it is feasible to detect early signs of cortical atrophy among individuals who are at high risk for developing schizophrenia. Fifteen individuals at high-risk for schizophrenia and 15 of their first degree relatives diagnosed with schizophrenia were compared with controls (n=25) who did not have a family history of psychiatric illness or psychiatric hospitalizations. On the basis of a voxelwise analysis of apparent diffusion coefficient (ADC) maps derived from diffusion weighted magnetic resonance imaging, these individuals showed evidence of deficits in four separate regions of the brain, all on the left side only: parahippocampal gyrus, lingual gyrus, superior frontal gyrus, and middle frontal gyrus. However, conventional volumetric quantification of ventricular space to detect atrophy failed to reveal differences between high-risk subjects and controls. It is concluded that ADC may be a more sensitive measure than ventricular volume assessments for use in future studies of early prediction of schizophrenia.

An fMRI study of language processing in people at high genetic risk for schizophrenia

BACKGROUND Abnormalities in language processing and the related brain structures have been reported in people with schizophrenia. It has been proposed that the brain pathways for language processing are anomalous in these individuals and form the underlying basis for the positive symptoms of the illness. If language pathway abnormalities can be detected early in people at high-risk for schizophrenia prior to the onset of symptoms, early treatment can ensue. METHODS Fifteen young adults at high genetic risk for developing schizophrenia were compared with 15 of their siblings with schizophrenia or schizoaffective disorder and 15 age and sex matched individuals at low risk for schizophrenia using a visual lexical decision task during fMRI. The data were analyzed by contrasting activation obtained during a real word-pseudoword discrimination task to activation obtained during a nonlinguistic discrimination task, and the differential activations were examined. RESULTS Patterns of brain activation while reading and discriminating between real and pseudowords differed across groups, with more bilateral activation in schizophrenia patients and their high-risk siblings than controls. In control subjects discrimination of words from psuedowords significantly activated Brodmanns area 44 more strongly than when non-linguistic symbols were discriminated. However, high-risk subjects and their siblings with schizophrenia activated this region similarly for both language and non-language tasks. CONCLUSIONS Normal individuals can be distinguished from subjects at high genetic risk for schizophrenia and patients with schizophrenia by their more lateralized and stronger activation of Brodmanns area 44 to word compared with symbol discrimination tasks. Thus, evaluation of language processing by fMRI may be a valuable tool for use in the prediction of individual risk for developing schizophrenia.

Hydraulic model of myogenic autoregulation and the cerebrovascular bed: the effects of altering systemic arterial pressure.

Systemic arterial (Ps), cerebrospinal fluid (Pcsf), and sagittal sinus (Pss) pressures were measured in 39 dogs divided into eight groups in which Ps was altered pharmacologically or by bleeding. The pharmaceuticals used were norepinephrine (N-EP), dopamine (DOP), sodium nitroprusside (SNP), and nitroglycerin (NTG). SNP and NTG were examined with and without methohexital (MHX) anesthesia and during chronic infusion and bolus injection. The various pressures were subjected to systems analysis in accordance with a previously published model of myogenic autoregulation. Myogenic autoregulation seemed to be impaired only during infusions of N-EP, DOP, and SNP without MHX and during hypovolemic hypotension. The various observed changes in Pcsf are explained by using a hydraulic model of the cerebrovascular bed in which Pcsf represents the pressure drop across the outflow resistance of the bridging veins and lateral lacunae and myogenic autoregulation at the arteries and arterioles represents the major inflow resistance. Impaired myogenic autoregulation is associated with a rise in Pcsf. In addition, variation in pulse pressure is demonstrated to be related to the arterial pulse pressure and the degree of arterial and arteriolar vasodilation.

In Vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spin-spin (T(2)) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75(NTR) and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre- and postsynaptic profiles in these target areas. T(2) effects were negligible in Ts1Cje mice that are diploid for App and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimers disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations.

Cerebral blood flow measured by NMR indicator dilution in cats.

We developed techniques to assess the utility of a nuclear magnetic resonance (NMR) indicator for cerebral blood flow studies in cats, using Freon-22 for the first candidate. A PIN-diode-switched NMR experiment allowed the acquisition of an arterial as well as a cerebral fluorine-19 signal proportional to concentration vs. time in a 1.89 T magnet. Mean +/- SD blood:brain partition coefficients for Freon-22 were estimated at 0.93 +/- 0.08 for gray matter and 0.77 +/- 0.12 for white matter. Using maximum-likelihood curve fitting, estimates of mean +/- SD resting cerebral blood flow were 50 +/- 19 ml/100 g-min for gray matter and 5.0 +/- 2.0 ml/100 g-min for white matter. Hypercapnia produced the expected increases in gray and white matter blood flow. The physiologic effects of Freon-22, including an increase in cerebral blood flow itself with administration of 40% by volume, may limit its use as an indicator. Nevertheless, the NMR techniques described demonstrate the feasibility of fluorine-19-labeled compounds as cerebral blood flow indicators and the promise for their use in humans.

Pulsed arterial spin labeling using TurboFLASH with suppression of intravascular signal

Accurate quantification of perfusion with the ADC techniques requires the suppression of the majority of the intravascular signal. This is normally achieved with the use of diffusion gradients. The TurboFLASH sequence with its ultrashort repetition times is not readily amenable to this scheme. This report demonstrates the implementation of a modified TurboFLASH sequence for FAIR imaging. Intravascular suppression is achieved with a modified preparation period that includes a driven equilibrium Fourier transform (DEFT) combination of 90°–180°–90° hard RF pulses subsequent to the inversion delay. These pulses rotate the perfusion‐prepared magnetization into the transverse plane where it can experience the suitably placed diffusion gradients before being returned to the longitudinal direction by the second 90° pulse. A value of b = 20–30 s/mm2 was thereby found to suppress the majority of the intravascular signal. For single‐slice perfusion imaging, quantification is only slightly modified. The technique can be readily extended to multislice acquisition if the evolving flow signal after the DEFT preparation is considered. An advantage of the modified preparation scheme is evident in the multislice FAIR images by the preservation of the sign of the magnetization difference. Magn Reson Med 49:341–350, 2003.