Targeting anxiety to improve quality of life in patients with schizophrenia.

BACKGROUND: Several studies suggested that anxiety can significantly affect the outcome of schizophrenia. Despite this evidence, non-pharmacological interventions targeting anxiety are still heterogenous. This study aims to test the efficacy of a novel training specifically designed to target anxiety in patients with schizophrenia. Innovatively, this training, beyond psychoeducation and problem solving, also targets Theory of Mind, as it provides coping strategies. METHOD: Twenty-seven outpatients with schizophrenia received a novel rehabilitative training targeting anxiety (Anxiety Management Group [AMG]) combined with a Computer-Assisted Cognitive Remediation (CACR), and twenty received CACR plus a control intervention (Control Newspaper discussion Group [CNG]). All patients were assessed at baseline and after treatment for quality of life, neurocognition and anxiety. RESULTS: After training, patients treated with AMG+CACR showed significantly greater improvements on anxiety. A significant increase in quality of life was observed only for AMG+CACR group. Moreover, the participants' appraisal showed a significant difference between treatment groups with higher ratings among patients who received the AMG+CACR. CONCLUSIONS: This study thus suggests feasibility and efficacy of the proposed intervention, that could be implemented in rehabilitative programs for patients with schizophrenia with potential benefits also on disease course and outcome.

Cognitive remediation and functional improvement in schizophrenia: Is it a matter of size?

BACKGROUND: Cognitive Remediation represents the best available tool to treat cognitive deficits in schizophrenia and evidence suggests an effect also on global functioning. However, the relationship between cognitive and functional improvement is not yet fully elucidated: do cognitive changes need to be of a definite size and/or encompass a certain number of domains in order to impact on daily functioning? This study aims to explore the role of cognitive improvement, evaluated both quantitatively and qualitatively through the use of Italian equivalent scores, on the daily functioning of patients. As secondary goal, the influence of demographic, clinical and neuropsychological variables on functional outcome was also systematically investigated. METHODS: One hundred subjects with a diagnosis of schizophrenia underwent 36 sessions of Cognitive Remediation and were evaluated at baseline and after the training with the Brief Assessment of Cognition in Schizophrenia and the Quality of Life Scale. RESULTS: A total of 70% of patients improved in at least one cognitive domain and over 50% obtained a normalized score. Among the clinical and neurocognitive factors examined, the only significant predictor of quality of life's improvement was the proportion of cognitive functions that reached an equivalent score of "normal". CONCLUSIONS: This study suggests that improvements in daily functioning depend on the achievement of a cognitive profile as much as possible "normal", harmonious and balanced, supporting the idea that a qualitative leap in cognition is needed in order to gain an advantage in real life activities.

Combined social cognitive and neurocognitive rehabilitation strategies in schizophrenia: neuropsychological and psychopathological influences on Theory of Mind improvement.

BACKGROUND: Neurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables. METHOD: Seventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG). RESULTS: ANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM. CONCLUSION: Results showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia.

Combined neurocognitive and metacognitive rehabilitation in schizophrenia: Effects on bias against disconfirmatory evidence.

BACKGROUND: A Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement. METHODS: Fifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE. RESULTS: After MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures. CONCLUSIONS: This study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients.

Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia.

Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter.

CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia.

Induced pluripotent stem cells (iPSC) offer a unique opportunity for developmental studies, disease modeling and regenerative medicine approaches in humans. The aim of our study was to create an in vitro 'patient-specific cell-based system' that could facilitate the screening of new therapeutic molecules for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited form of fatal arrhythmia. Here, we report the development of a cardiac model of CPVT through the generation of iPSC from a CPVT patient carrying a heterozygous mutation in the cardiac ryanodine receptor gene (RyR2) and their subsequent differentiation into cardiomyocytes (CMs). Whole-cell patch-clamp and intracellular electrical recordings of spontaneously beating cells revealed the presence of delayed afterdepolarizations (DADs) in CPVT-CMs, both in resting conditions and after ß-adrenergic stimulation, resembling the cardiac phenotype of the patients. Furthermore, treatment with KN-93 (2-[N-(2-hydroxyethyl)]-N-(4methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), an antiarrhythmic drug that inhibits Ca(2+)/calmodulin-dependent serine-threonine protein kinase II (CaMKII), drastically reduced the presence of DADs in CVPT-CMs, rescuing the arrhythmic phenotype induced by catecholaminergic stress. In addition, intracellular calcium transient measurements on 3D beating clusters by fast resolution optical mapping showed that CPVT clusters developed multiple calcium transients, whereas in the wild-type clusters, only single initiations were detected. Such instability is aggravated in the presence of isoproterenol and is attenuated by KN-93. As seen in our RyR2 knock-in CPVT mice, the antiarrhythmic effect of KN-93 is confirmed in these human iPSC-derived cardiac cells, supporting the role of this in vitro system for drug screening and optimization of clinical treatment strategies.

High-frequency transcutaneous peripheral nerve stimulation induces a higher increase of heat pain threshold in the cutaneous area of the stimulated nerve when confronted to the neighbouring areas.

BACKGROUND: TENS (transcutaneous electrical nerve stimulation) is probably the most diffused physical therapy used for antalgic purposes. Although it continues to be used by trial and error, correct targeting of paresthesias evoked by the electrical stimulation on the painful area is diffusely considered very important for pain relief. AIM: To investigate if TENS antalgic effect is higher in the cutaneous area of the stimulated nerve when confronted to neighbouring areas. METHODS: 10 volunteers (4 males, 6 females) underwent three different sessions: in two, heat pain thresholds (HPTs) were measured on the dorsal hand skin before, during and after electrical stimulation (100 Hz, 0.1 msec) of superficial radial nerve; in the third session HPTs, were measured without any stimulation. RESULTS: Radial nerve stimulation induced an increase of HPT significantly higher in its cutaneous territory when confronted to the neighbouring ulnar nerve territory, and antalgic effect persisted beyond the stimulation time. CONCLUSIONS: The location of TENS electrodes is crucial for obtaining the strongest pain relief, and peripheral nerve trunk stimulation is advised whenever possible. Moreover, the present study indicates that continuous stimulation could be unnecessary, suggesting a strategy for avoiding the well-known tolerance-like effect of prolonged TENS application.

Dynamic MR imaging of the temporomandibular joint using a balanced steady-state free precession sequence at 3T.

The aim of our project was to develop an MR imaging protocol for dynamic imaging of the TMJ. We imaged a total of 24 joints in 12 subjects. We developed an imaging protocol on a 3T system using the true FISP sequence that yielded an acceptable spatial and temporal resolution for dynamic MR imaging.

Chronic pain: not only a matter of time.

The term "chronic" is often used in daily clinical practice to indicate a type of pain that lasts over time and is accompanied by diagnostic and therapeutic difficulties. The common feeling is that in this category are actually collected many different clinical cases with the unique characteristic that the pain lasts a long time. It follows that treatment failures are common and patients roam from doctor to doctor in search of an effective care program. At the same time the health spending for the treatment of these patients is becoming increasingly high. In clinical practice we meet many patients with obscure pain syndromes which are classified as "chronic" and untreatable only because persist for long time and that obtain a complete pain relief after a right diagnosis and a specific treatment. In this review the Authors want to argue that the term chronic should not be used only when the pain persists for some time or just when signs and symptoms of mechanisms in the central nervous systems are present. The authors suggest that there is a clear difference between acute and chronic pain but also that in chronic pain patients there are three different painful conditions: 1) patients with a chronic disease (or sequelae) and with chronic pain in which the pain mechanisms are closely related to the underlying chronic disease (e.g., rheumatoid arthritis) or to previous injury that has generated other unsolvable mechanisms (e.g., deafferentation pain after plexus avulsion); 2) patients with a chronic disease and chronic pain in which new mechanisms overlap those related to the underlying disease; 3) patients with chronic pain in whom the correlation between pain and the initial tissue injury is lost and the persistence of pain is due to new developed mechanisms. According to this classification we can distinguish patients with "painful chronic disease" by patients with "independent chronic pain". In these latter cases the complexity of the clinical picture is to be found in a maladaptative response to pain, in emergence of central nervous system mechanisms and in behavioral changes that, in turn, can cause long-term social, psychological and physical sequelae. Differences among patients in developing chronic pain can be related to differences in the ability of the brain to continuously adapt its functional and structural organization. It is obvious that the care plan for these complex patients is profoundly different from that needed for patients with pain linked to a chronic disease or stabilized pain mechanisms. The purpose of the present article is to provide a review of the most noteworthy developments in this field and to propose some observations that may help to understand this pain condition and the patients.

Inhibition of somatosensory evoked potentials during spinal cord stimulation and its possible role in the comprehension of antalgic mechanisms of neurostimulation for neuropathic pain.

BACKGROUND: Spinal cord stimulation (SCS) has been widely used for pain relief of patients with neuropathic chronic pain, frequently with only partial efficacy. Further advancements probably need a better understanding of SCS mechanisms, yet largely unknown. Aims of this paper were to answer the question if the lumbar SCS inhibits the tibial nerve somatosensory evoked potentials (SEPs) and to discuss the role of lemniscal afferents modulation in the antalgic mechanism of SCS. METHODS: Ten consecutive patients successfully treated with implanted SCS devices for chronic pain in the lower limbs (four males, six females, age range 42-72 years) were enrolled. All the patients had an implanted system with an epidural lead connected to a pulse generator. The vertebral level ranged from T9 to T12. The cortical SEPs complex P39-N50-P60 was recorded at the basal (T0) evaluation, during the stimulation (T1) and immediately after the stimulation (T2). RESULTS: In two of ten patients (20%) the complex P39-N50-P60 became unrelievable at the T1 control (stimulator on). In the remaining eight patients statistical analysis showed a significant reduction of the P39/N50 amplitude at T1 recording. In all patients considered, T0 and T2 recordings were not significantly different, suggesting a fast recovery of the SCS effect on SEPs. CONCLUSION: The results obtained in the present study show an inhibitory effect of SCS on SEPs and support the hypothesis that in some forms of neuropathic pain the antalgic effect of SCS could be attributed to the collision of action potentials travelling in opposite direction on peripheral large diameter fibres.

Spatial inhibition and the visual cortex: a magnetic resonance spectroscopy imaging study.

INTRODUCTION: Deficits in processing spatial information have been observed in clinical populations who have abnormalities within the dopamine (DA) system. As psychostimulants such as methamphetamine (MA) are particularly neurotoxic to the dopaminergic system it was of interest to examine the performance of MA-dependent individuals on a task of spatial attention. METHOD: 51 MA-dependent subjects and 22 age-matched non-substance abusing control subjects were tested on a Spatial Stroop attention test. MR Spectroscopy (MRS) imaging data were analyzed from 32 MA abusers and 13 controls. RESULTS: No group differences in response time or accuracy emerged on the behavioral task with both groups exhibiting equivalent slowing when the word meaning and the spatial location of the word were in conflict. MRS imaging data from the MA abusers revealed a strong inverse correlation between NAA/Cr ratios in the Primary Visual Cortex (PVC) and spatial interference (p=0.0001). Moderate inverse correlations were also seen in the Anterior Cingulate Cortex (ACC) (p=0.02). No significant correlations were observed in the controls, perhaps due to the small sample of imaging data available (n=13). DISCUSSION: The strong correlation between spatial conflict suppression and NAA/Cr levels within the PVC in the MA-dependent individuals suggests that preserved neuronal integrity within the PVC of stimulant abusers may modulate cognitive mechanisms that process implicit spatial information.

Progressive decrease in N-acetylaspartate/Creatine ratio in a teenager with type 1 diabetes and repeated episodes of ketoacidosis without clinically apparent cerebral edema: Evidence for permanent brain injury.

Recent data suggest that DKA may contribute to cognitive impairment in children with type 1 DM. We measured the NAA/Cr ratio in a teenager during and following 2 separate episodes of DKA without clinically apparent cerebral edema. The NAA/Cr ratio decreased during DKA and improved following recovery. However, the NAA/Cr value was lower after the second episode of DKA (1.76) than after the first (1.97). These findings provide support for the hypothesis that neuronal injury may result from DKA.

Regional pattern of white matter microstructural changes in normal aging, MCI, and AD.

OBJECTIVE: To cross-sectionally compare the regional white matter fractional anisotropy (FA) of cognitively normal (CN) older individuals and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), separately focusing on the normal-appearing white matter (NAWM) and white matter hyperintensities (WMH), and to test the independent effects of presumed degenerative and vascular process on FA differences. METHODS: Forty-seven patients with AD, 73 patients with MCI, and 95 CN subjects received diffusion tensor imaging and vascular risk evaluation. To properly control normal regional variability of FA, we divided cerebral white matter into 4 strata as measured from a series of young healthy individuals (H1 = highest; H2 = intermediate high; H3 = intermediate low; H4 = lowest anisotropy stratum). RESULTS: For overall cerebral white matter, patients with AD had significantly lower FA than CN individuals or patients with MCI in the regions with higher baseline anisotropy (H1, H2, and H3), corresponding to long corticocortical association fibers, but not in H4, which mostly includes heterogeneously oriented fibers. Vascular risk showed significant independent effects on FA in all strata except H1, which corresponds to the genu and splenium of the corpus callosum. Similar results were found within NAWM. FA in WMH was significantly lower than NAWM across all strata but was not associated with diagnosis or vascular risk. CONCLUSIONS: Both vascular and Alzheimer disease degenerative process contribute to microstructural injury of cerebral white matter across the spectrum of cognitive ability and have different region-specific injury patterns.

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study.

Converging evidence suggests that patients with panic disorder have a metabolic disturbance that may influence the regulation of arousal systems and confer vulnerability to 'spontaneous' panic attacks. The consistent finding of elevated brain lactate responses to various metabolic challenges in panic disorder appears to support this model, although the mechanism of this effect is not understood. Several mechanisms have been proposed to account for elevated brain lactate responses in panic disorder, including (1) brain hypoxia due to excessive cerebral vasoconstriction, and (2) a metabolic disturbance affecting lactate metabolism. Recent studies have shown that neural activation (for example, sensory stimulation) causes local lactate accumulation in the presence of increased oxygen availability. The current study used proton magnetic resonance spectroscopic measures of visual cortex lactate changes during visual stimulation in 15 untreated patients with panic disorder and 15 matched volunteers to critically test these two proposed mechanisms of elevated brain lactate responses in panic disorder. Visual cortex lactate/N-acetylaspartate increased during visual stimulation in both groups. The increase was significantly greater in the panic patients than in the comparison group. There were no group differences in end-tidal pCO(2). The finding that visual stimulation leads to significantly greater visual cortex lactate responses in panic patients is not predicted by the hypoxia model. These results suggest that a metabolic disturbance affecting the production or clearance of lactate is the cause of the elevated brain lactate responses consistently observed in panic disorder and provide further support for metabolic models of vulnerability to this illness.

Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis.

BACKGROUND AND PURPOSE: Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury. MATERIALS AND METHODS: Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods. RESULTS: In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region. CONCLUSIONS: NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.

Increase of the heat pain threshold during and after high-frequency transcutaneous peripheral nerve stimulation in a group of normal subjects.

AIM: Transcutaneous electrical nerve stimulation (TENS) is used worldwide for pain relief, but its mechanisms of action are not completely understood. High frequency transcutaneous peripheral nerve stimulation (HF-TPNS) is a term describing a type of TENS where a peripheral nerve is stimulated transcutaneously. The aim of the investigation was to verify the hypothesis that HF-TPNS increases the heat pain threshold in the skin territory of the stimulated nerve, during and after stimulation. METHODS: Eighteen volunteers (8 men, 10 women) participated in 2 sessions conducted on different days. In each session their heat pain thresholds were measured in basal conditions and after 5, 10, 15, 25, 40, 70 min. In one session, HF-TPNS was delivered for 10 min immediately after basal evaluation (HF-TPNS session). In the other session the heat pain thresholds only were measured (control session). The superficial radial nerve was stimulated at the wrist (frequency of 100 Hz, pulse duration of 0.1 ms). The heat pain threshold was studied using a contact thermode (surface of 12.5 cm(2)) placed in the cutaneous area of the stimulated nerve at the site where the paresthesia evoked by electrical stimulation could be felt. RESULTS: HF-TPNS significantly increased the heat pain threshold both during and after stimulation. CONCLUSION: This study confirms that HF-TPNS induces an important hypoalgesic effect. The prolonged duration of poststimulation hypoalgesia (60 min) indicates that continuous stimulation is probably unnecessary. Further studies are needed to test the hypothesis that intermittent HF-TPNS is able to maintain its hypoalgesic effectiveness over time.

Are hot-burning sensations produced by the axonal damage of afferent unmyelinated fibres?

AIM: Pain resulting from nerve lesions is classically referred to as a ''burning pain''. Both the axonal damage and sensitization of unmyelinated C-fibres have been considered as the possible generators of this sensation. The aim of this study was to verify the hypothesis that hot-burning sensations are produced by the axonal damage of afferent unmyelinated fibres in peripheral nerves. METHODS: A total of 122 patients with pain localised in the distal parts of the upper limbs (hand, forearm) and lower limbs (leg or foot) were enrolled in the study. The intensity of pain and hot-burning sensations was measured using a numerical scale (range 0-10). The relationship between the presence of warm hypoesthesia (related to the loss of afferent unmyelinated fibres) and hot-burning sensations was assessed. Warm hypoesthesia was identified by Quantitative Sensory Testing employing thermal stimulation (QST-t) and the patients were divided into 2 groups: group A, with hypoesthesia and group B with normoesthesia. Patients with a central nervous impairment were excluded. RESULTS: No significant differences in the intensity of pain and hot-burning sensations was observed between the group of patients with warm hypoesthesia and that with warm normoesthesia. CONCLUSIONS: This study does not confirm the hypothesis that hot-burning sensations are produced by the axonal damage of afferent amyelinated fibres in peripheral nerves. It agrees with clinical evidence suggesting that patients with different clinical conditions can complain of hot-burning sensations, independently of the presence of a nerve lesion.

Intrasubject reproducibility of functional MR imaging activation in language tasks.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the reproducibility of functional MR imaging (fMRI) activation (volume and laterality) within both inferior frontal and temporoparietal regions of interest for both receptive and expressive language tasks. METHODS: Ten healthy volunteers participated in fMRI experiments for 6 language tasks: verb generation, confrontation naming, semantic decision making, visual sentence comprehension, auditory sentence comprehension, and story listening. Each subject was scanned during 2 separate sessions separated by a minimum of 4 weeks. Laterality of activation was defined by laterality indices (LIs), which were calculated by 2 methods: one method based on the measured volume of activation and the other method based on the F statistic of the activation. Reproducibility was calculated by using concurrence ratios for the volume of activation (R(overlap), R(volume)) and test-retest correlation for LIs. RESULTS: All tasks generated reproducible LIs within at least one of the regions of interest, but verb generation produced the highest test-retest correlations (r = 0.99) within both regions of interest. Verb generation was associated with the highest average concurrence ratios within the inferior frontal region of interest (R(overlap) = 45.2; R(volume) = 70.9). In general, the concurrence ratios were lower within the temporoparietal region of interest compared with the inferior frontal region of interest. LIs calculated with F statistics were more reproducible than the LIs calculated by activation volume. CONCLUSION: fMRI is able to provide reproducible LIs in both inferior frontal and temporoparietal regions for assessing hemispheric dominance in language processing. The volume of activation, especially within the temporoparietal regions, is less reproducible than the laterality of activation, so the former should be used with caution.

MRI-based technique for determining nonuniform deformations throughout the volume of articular cartilage explants.

Articular cartilage is critical to the normal function of diarthrodial joints. Despite the importance of the tissue and the prevalence of cartilage degeneration (e.g., osteoarthritis), the technology required to noninvasively describe nonuniform deformations throughout the volume of the tissue has not been available until recently. The objectives of the work reported in this paper were to 1) describe a noninvasive technique (termed the cartilage deformation by tag registration (CDTR) technique) to determine nonuniform deformations in articular cartilage explants with the use of specialized MRI tagging and image processing methods, 2) evaluate the strain error of the CDTR technique using a custom MRI-compatible phantom material, and 3) demonstrate the applicability of the CDTR technique to articular cartilage by determining 3D strain fields throughout the volume of a bovine articular cartilage explant. A custom MRI pulse sequence was designed to tag and image articular cartilage explants at 7 Tesla in undeformed and deformed states during the application of multiple load cycles. The custom pulse sequence incorporated the "delays alternating with nutations for tailored excitation" (DANTE) pulse sequence to apply tags. This was followed by a "fast spin echo" (FSE) pulse sequence to create images of the tags. The error analysis using the phantom material indicated that deformations can be determined with an error, defined as the strain precision, better than 0.83% strain. When this technique was applied to a single articular cartilage explant loaded in unconfined compression, hetereogeneous deformations throughout the volume of the tissue were evident. This technique potentially can be applied to determine normal cartilage deformations, analyze degenerated cartilage, and evaluate cartilage surgical repair and treatment methodologies. In addition, this technique may be applied to other soft tissues that can be appropriately imaged by MR.