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Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia.

BACKGROUND: Two brain regions often implicated in schizophrenia are the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF). It has been hypothesized that the pathophysiology of the disorder might involve an alteration of functional interactions between medial temporal and prefrontal areas. METHODS: We used neuroimaging data acquired during a working memory challenge and a sensorimotor control task in 22 medication-free schizophrenic patients and 22 performance-, age-, and sex-matched healthy subjects to investigate "functional connectivity" between HF and DLPFC in schizophrenia. The HF blood flow, measured with positron emission tomography, was assessed within a probabilistic template. Brain areas whose activity was positively or negatively coupled to HF were identified using voxelwise analysis of covariance throughout the entire brain and analyzed using a random effects model. RESULTS: During working memory, patients showed reduced activation of the right DLPFC and left cerebellum. In both groups, inverse correlations were observed between the HF and the contralateral DLPFC and inferior parietal lobule. While these did not differ between diagnostic groups during the control task, the working memory challenge revealed a specific abnormality in DLPFC-HF functional connectivity-while the right DLPFC was significantly coupled to the left HF in both groups during the control task, this correlation was not seen in healthy subjects during working memory but persisted undiminished in patients, resulting in a significant task-by-group interaction. CONCLUSIONS: Our results suggest a regionally specific alteration of HF-DLPFC functional connectivity in schizophrenia that manifests as an unmodulated persistence of an HF-DLPFC linkage during working memory activation. Thus, a mechanism by which HF dysfunction may manifest in schizophrenia is by inappropriate reciprocal modulatory interaction with the DLPFC.

Adult↗

A comparison of structured sensorimotor therapy and child-centered activity in the treatment of preschool children with sensorimotor problems.

This study compared the benefits of a child-centered therapy approach emphasizing child-initiated play interactions within a structured therapy environment to those of a therapist-directed, structured sensorimotor therapy approach in 12 preschool children with sensorimotor dysfunction. Each child received a pretest, 8 weeks of intervention (A or B) provided once weekly for a 1-hr session, a retest, 8 weeks of intervention (B or A) provided once weekly, and a final retest. A case study methodology was used to evaluate outcome data. Structured sensorimotor therapy was more useful than child-centered therapy in promoting gross motor skills, functional abilities (i.e., self-care), and sensory integrative functions. Child-centered therapy appeared to promote fine motor skills better. Although there were no differences in the two therapies for gains in play, attention, and behavior, variables such as temperament, attentional abilities, family stress, severity of sensorimotor delay, and whether the child had received treatment before seemed to affect which therapy was more beneficial for behavior, play, and attention. The effect of the findings on therapeutic practice is discussed.

Affective Symptoms↗

Vascular syndromes of the thalamus.

BACKGROUND: This article reviews the anatomy, connections, and functions of the thalamic nuclei, their vascular supply, and the clinical syndromes that result from thalamic infarction. SUMMARY OF REVIEW: Thalamic nuclei are composed of 5 major functional classes: reticular and intralaminar nuclei that subserve arousal and nociception; sensory nuclei in all major domains; effector nuclei concerned with motor function and aspects of language; associative nuclei that participate in high-level cognitive functions; and limbic nuclei concerned with mood and motivation. Vascular lesions destroy these nuclei in different combinations and produce sensorimotor and behavioral syndromes depending on which nuclei are involved. Tuberothalamic territory strokes produce impairments of arousal and orientation, learning and memory, personality, and executive function; superimposition of temporally unrelated information; and emotional facial paresis. Paramedian infarcts cause decreased arousal, particularly if the lesion is bilateral, and impaired learning and memory. Autobiographical memory impairment and executive failure result from lesions in either of these vascular territories. Language deficits result from left paramedian lesions and from left tuberothalamic lesions that include the ventrolateral nucleus. Right thalamic lesions in both these vascular territories produce visual-spatial deficits, including hemispatial neglect. Inferolateral territory strokes produce contralateral hemisensory loss, hemiparesis and hemiataxia, and pain syndromes that are more common after right thalamic lesions. Posterior choroidal lesions result in visual field deficits, variable sensory loss, weakness, dystonia, tremors, and occasionally amnesia and language impairment. CONCLUSIONS: These vascular syndromes reflect the reciprocal cerebral cortical-thalamic connections that have been interrupted and provide insights into the functional properties of the thalamus.

Animals↗

Cortical reorganization in the aging brain.

Aging exerts major reorganization and remodeling at all levels of brain structure and function. Studies in aged animals and in human elderly individuals demonstrate that sensorimotor cortical representational maps undergo significant alterations. Because cortical reorganization is paralleled by a decline in perceptual and behavioral performance, this type of cortical remodeling differs from the plastic reorganization observed during learning processes in young individuals where map changes are associated with a gain in performance. It is now clear that brain plasticity is operational into old age; therefore, protocols for interventions such as training, exercising, practicing, and stimulation, which make use of neuroplasticity principles, are effective to ameliorate some forms of cortical and behavioral age-related changes, indicating that aging effects are not irreversible but treatable. However, old individuals cannot be rejuvenated, but restoration of function is possible through the emergence of new processing strategies. This implies that cortical reorganization in the aging brain occurs twice: during aging, and during treatment of age-related changes.

Aging↗

Abnormal plasticity of the sensorimotor cortex to slow repetitive transcranial magnetic stimulation in patients with writer's cramp.

Previous studies demonstrated functional abnormalities in the somatosensory system, including a distorted functional organization of the somatosensory cortex (S1) in patients with writer's cramp. We tested the hypothesis that these functional alterations render S1 of these patients more susceptible to the "inhibitory" effects of subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) given to S1. Seven patients with writer's cramp and eight healthy subjects were studied. Patients also received rTMS to the motor cortex hand area (M1). As an outcome measure, short-latency afferent inhibition (SAI) was tested. SAI was studied in the relaxed first dorsal interosseous muscle using conditioning electrical stimulation of the index finger and TMS pulses over the contralateral M1. Baseline SAI did not differ between groups. S1 but not M1 rTMS reduced SAI in patients. rTMS had no effects on SAI in healthy subjects. Because SAI is mediated predominantly at a cortical level in the sensorimotor cortex, we conclude that there is an abnormal responsiveness of this area to 1 Hz rTMS in writer's cramp, which may represent a trait toward maladaptive plasticity in the sensorimotor system in these patients.

Adult↗

Axonal plasticity is associated with motor recovery following amphetamine treatment combined with rehabilitation after brain injury in the adult rat.

Clinical and laboratory studies have suggested that amphetamine treatment when paired with rehabilitation results in improved recovery of function after stroke or traumatic brain injury. In the present study, we investigated whether new anatomical pathways developed in association with improved motor function after brain damage and amphetamine treatment linked with rehabilitation. Following a unilateral sensorimotor cortex lesion in the adult rat, amphetamine (2 mg/kg) was administered in conjunction with physiotherapy sessions on postoperative days two and five. Physiotherapy was continued twice daily for the first 3 weeks after injury, and then once daily until week six. Performance on skilled forelimb reaching and ladder rung walking was used to assess motor improvement. Our results show that animals with sensorimotor cortical lesions receiving amphetamine treatment linked with rehabilitation had significant improvement in both tasks. Neuroanatomical tracing of efferent pathways from the opposite, non-damaged cortex resulted in the novel finding that amphetamine treatment linked with rehabilitation, significantly increased axonal growth in the deafferented basilar pontine nuclei. These results support the notion that pharmacological interventions paired with rehabilitation can enhance neuronal plasticity and thereby improve functional recovery after CNS injury.

Amphetamine↗

Neurophysiological techniques as an aid to surgical treatment of primary brain tumors.

We describe a method of cortical stimulation for localizing functional areas of brain before operation for primary brain tumors that was carried out in 14 patients. The method is unique in that the stimulation is done over several days using chronically indwelling subdural electrode arrays. In addition to cortical stimulation findings, somatosensory evoked potentials were helpful in locating the sensorimotor strip. The neurophysiological data have allowed an aggressive neurosurgical attack without producing a functional deficit.

Adolescent↗

Can lateralizing sensorimotor deficits be identified after neonatal cerebral hypoxia-ischemia in rats?

The neonatal rat model of unilateral cerebral hypoxia-ischemia (HI) is commonly used to test the efficacy of therapeutic strategies for prevention or treatment of stroke in the immature brain. Traditionally neuroprotection has been defined as reduction in tissue injury; there is growing interest in complementary functional assessment. Our objectives were to determine whether lateralizing performance deficits could be detected in two sensorimotor tests not previously used after neonatal HI, and to determine whether performance reflected the extent of tissue damage. Seven-day-old rats that underwent right carotid ligation followed by 1.5 h in 8% O2 and age-matched controls were tested for sensorimotor performance on postnatal day 35 (P35). We evaluated initial forepaw placement on the wall of a cylinder, and time taken to contact and remove adhesive stickers from the dorsum of each forepaw. Cortical, striatal and hippocampal damage severity was evaluated on P36 by calculating the contralateral-ipsilateral percent difference in regional areas. There was an inverse relationship between cortical and striatal damage severity and percent contralateral forepaw initiation in the cylinder. There was a direct linear relationship between damage severity and the delay from contact to removal of the contralateral sticker. These two tests revealed quantifiable contralateral sensorimotor deficits 4 weeks after unilateral neonatal cerebral HI in animals with cortical and striatal damage.

Animals↗

Integration of functional brain mapping in image-guided neurosurgery.

Magnetoencephalographic (MEG) brain mapping was performed in 90 patients with lesions associated with eloquent sensorimotor cortex. The MEG-derived sensorimotor mapping information was utilised for risk analysis and planning. Subsequently, these patients underwent either stereotactic volumetric resection, stereotactic biopsy or non-surgical management of their lesions. In seventeen patients, the MEG sensorimotor localization was integrated into an operative stereotactic database (consisting of CT, MRI and digital angiography) to be used in an interactive fashion during computer-assisted stereotactic volumetric resection procedures. The spatial relationship between the MEG derived functional anatomy, the structural/radiological anatomy and the pathology could then be viewed simultaneously, thereby affording a safer trajectory and approach. In addition, the real-time availability of functional mapping information in an interactive fashion helped reduce surgical risk and minimise functional morbidity. All of these patients had resection of their lesions with no change in their neurological status. In conclusion, MEG is a non-invasive, accurate, and reproducible method for pre-operative assessment of patients with lesions associated with eloquent sensory and motor cortex. The interactive use of MEG functional mapping in the operating room can allow for a safer approach and resection of these eloquent cortex lesions.

Adolescent↗

Effects of cerebral ischemia on evoked cerebral blood oxygenation responses and BOLD contrast functional MRI in stroke patients.

BACKGROUND AND PURPOSE: To evaluate the mechanisms of failure of blood oxygenation level-dependent (BOLD) imaging in stroke, we compared the evoked cerebral blood oxygenation (CBO) responses and activation volumes (AVs) of BOLD functional MRI (fMRI) in chronic stroke patients with moderate and severe cerebral ischemia. METHODS: We measured the evoked CBO responses in the primary sensorimotor cortex (PSMC) by means of near-infrared spectroscopy during contralateral motor tasks. We compared the AV of BOLD-functional MRI in the PSMC on the nonlesion and lesion sides. Single-photon emission computed tomography was used to classify ischemic status as moderate (slight reduction of regional cerebral blood flow and cerebrovascular reserve capacity [CVRC]) or severe (marked reduction of regional cerebral blood flow and CVRC; ie, misery perfusion). RESULTS: In age-matched controls, deoxyhemoglobin concentration decreased with concomitant increases in oxyhemoglobin and total hemoglobin concentrations during activation. The PSMC on the nonlesion side exhibited a normal CBO response pattern. On the lesion side, moderate cerebral ischemia did not affect the CBO response pattern, but severe cerebral ischemia caused an increase of deoxyhemoglobin during the task, associated with increases of oxyhemoglobin and total hemoglobin. Moderate cerebral ischemia induced only a slight reduction of the AV on the lesion side; however, severe cerebral ischemia markedly reduced the AV on the lesion side. The BOLD signal did not change in some areas of the PSMC on the lesion side in severe cerebral ischemia, whereas it tended to decrease in other areas during the tasks. CONCLUSIONS: Misery perfusion caused a marked reduction of the AV on BOLD imaging, associated with an increase of deoxyhemoglobin concentration during activation. BOLD-fMRI investigations of stroke patients should be performed while giving consideration to baseline circulatory status. Functional near-infrared spectroscopy could be an alternative means to assess the CVRC.

Adult↗

Mitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics.

In the present study, we have applied a novel strategy involving the postmortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c oxidase (COX; complex IV) to identify regional changes in energy metabolism in the basal ganglia of chronic, medicated schizophrenics. COX activity was decreased in the caudate nucleus but increased in the putamen and nucleus accumbens. An increase in succinate dehydrogenase (complex II) was evident in the putamen and nucleus accumbens, but changes were not seen with NADH dehydrogenase (complex I). An analysis of interregional correlations in energy metabolism revealed several anomalies in the connections between the caudate and putamen and the globus pallidus in schizophrenics. Results provide strong evidence that changes in baseline energy metabolism in specific regions of the basal ganglia may exist in the disease. Based upon the high degree of input it receives from associative cortical areas, results suggest that a defect in the caudate may underlie certain aspects of cognitive decline in schizophrenics. In contrast, an increase in COX in the putamen, which receives extensive projections from the sensorimotor cortex, may reflect an effect of chronic neuroleptic treatment on motor function.

Adult↗

Localized echo-volume imaging methods for functional MRI.

To perform true three-dimensional activation experiments in the human brain, dedicated localized echo-volume imaging (L-EVI) methods were developed. Three-dimensional acquisition allows generation of activation maps with minimal vascular enhancement related to inflow effects. The rapid acquisition of the L-EVI (approximately 100 msec) reduces signal instabilities caused by motion, facilitating the detection of the small intensity changes expected with brain activation. Single-shot L-EVI was performed on normal volunteers at 1.5 T, imaging a three-dimensional predefined volume (240 x 45 x 45 mm3) in the superior portion of the brain with a spatial resolution of 3.75 x 5 x 5 mm3. Increased brain coverage was achieved with a multi-volume imaging (three-shot) version, which simultaneously achieved effective suppression of signals from cerebrospinal fluid. In addition, both asymmetric spin-echo (ASE) and spin-echo (SE) versions of the technique were used to detect blood oxygenation level dependent (BOLD) signal changes in the motor cortex with a finger-tapping paradigm. Images obtained by the L-EVI sequence were qualitatively comparable to standard multislice two-dimensional echo-planar images. Both ASE and SE functional MRI (fMRI) experiments showed consistent activation in the contralateral primary sensorimotor cortex. Furthermore, significant differences in location and magnitude of activation was observed between the two methods, confirming theoretical predictions.

Brain Mapping↗

Further evidence of impaired position sense in knee osteoarthritis.

The knee joint position sense of a control group of healthy women was compared with that of women diagnosed as having severe osteoarthritis (OA) of the knee. Movements monitored were multi-joint when weightbearing on one leg. All subjects completed two angle rematching tests on two separate test occasions, and the criterion and reproduction angles which lay in the range of 15-45 degrees knee flexion were recorded photographically on each occasion. The results showed that the OA group performed the rematching tests with less accuracy than the controls (p < 0.05). Additionally, the OA group displayed significantly higher average flexion error magnitudes than the controls. These results suggest that joint position sense is less accurate and may be systematically distorted during multi-joint movements of the affected legs of a high proportion of women with severe knee OA. They further suggest that to improve their functional performance, patients with knee OA probably require a carefully constructed sensorimotor rehabilitation programme in which pain, effusion and fatigue are minimised.

Adolescent↗

The centre médian and parafascicular thalamic nuclei project respectively to the sensorimotor and associative-limbic striatal territories in the squirrel monkey.

The striatal projections of the centre médian (CM) and parafascicular (Pf) thalamic nuclei were examined in the squirrel monkey (Saimiri sciureus) by using the lectin wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) as an anterograde tracer. CM was found to project massively to the putamen, where terminal fields appeared principally in the form of oblique bands, and more diffusely to the dorsolateral border of the caudate nucleus. Striatal inputs from Pf were found more rostrally, especially in the ventromedial portion of the putamen, the entire ventromedial half of the caudate nucleus, and the ventral striatum including the nucleus accumbens and the olfactory tubercle. Pf terminal fields in the rostral striatum often displayed a patchy organization. Both CM and Pf projections were found to terminate in the matrix compartment of the striatum as defined by acetylcholinesterase staining. These results suggest that CM is more specifically involved in sensorimotor and Pf in associative and limbic aspects of basal ganglia function in primates.

Animals↗

Are lumbar repositioning errors larger among patients with chronic low back pain compared with asymptomatic subjects?

OBJECTIVE: To resolve the debate over whether lumbar repositioning acuity is reduced in patients with chronic low back pain (CLBP) by using a study design and methodology to minimize the effects of potential confounders. DESIGN: A single-blinded, controlled, multigroup comparative study. SETTING: Vocational rehabilitation center. PARTICIPANTS: Ninety-two patients with CLBP, divided into subgroups based on severity of symptoms and diagnostic characteristics. An age- and sex-matched group (n=31) of healthy subjects were the control. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured repositioning errors (variable, constant) at 3 positions of the lumbar spine. Subjects were guided to a sitting target posture and asked to perform lumbar flexion before reproducing the target posture. Self-assessed pain, self-efficacy, and functional ability were addressed through questionnaires. RESULTS: There were no differences in repositioning errors between the patients with CLBP or the subgroups of patients and the control group. We found only weak correlations between the repositioning errors and the self-reported data on functional disability, self-efficacy, and pain. CONCLUSIONS: We suggest that sensorimotor dysfunctions in CLBP should be evaluated with methods other than repositioning tests in order to generate data relevant to the development of rational diagnostic methods and rehabilitation programs.

Adult↗

Characteristics of behavioral abnormalities in alpha1d-adrenoceptors deficient mice.

To investigate the functional role of alpha1d-adrenergic receptor (alpha1d-AR) in the CNS, we have generated mutant mice lacking the alpha1d-AR using a gene targeting approach and examined in detail the effects of alpha1d-AR knockout mice on motor function, sensory function, and learning and memory. alpha1d-AR knockout mice showed better motor coordination at the highest rotating speed of the rotarod performance and stronger muscle tone using the traction meter, but their locomotor activity and swimming ability in the water maze were not affected. In the water maze requiring reference memory, alpha1d-AR knockout mice showed normal spatial learning. In the Y-maze task requiring working memory or attention, alpha1d-AR knockout mice displayed an impaired spontaneous alternation performance. The alpha1d-AR knockout mice tended to display lower levels of acoustic startle responses than the wild-type group at lower pulse intensities, although the acoustic prepulse inhibition was not impaired in the alpha1d-AR knockout mice. Furthermore, the NMDA receptor antagonist, MK-801-induced deficits of acoustic prepulse inhibition were not observed in the alpha1d-AR knockout mice. These results clearly demonstrate that the alpha1d-AR receptor plays an important role in the process of auditory sensory function, attention or working memory rather than reference memory, and the sensorimotor gating deficits induced by the NMDA receptor antagonist.

Acoustic Stimulation↗

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.

BACKGROUND: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. METHODS: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined. RESULTS: In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice. CONCLUSIONS: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

Animals↗

Vestibular control of skeletal geometry in the guinea pig: a problem of good trim?

Motor control of different segments of the body with multiple degrees of freedom appears to be coordinated by utilizing preferred axes of motor activity. This hypothesis may also be applied to vestibular control of posture. To explore this question we studied the anatomical relationship between the head and the cervical vertebral column by taking radiographs of the head-neck region in unrestrained alert guinea pigs. We determined that biomechanical constraints contribute to the stereotypical skeletal geometry observed in the resting animal and to a functional segmentation of the head-neck movement apparatus. Subsequent lesion studies of vestibular end organs with quantification of the resulting postural syndromes suggest that the functional segmentation of the cervical vertebral column corresponds to a functional partitioning of vestibular afferents. Our findings also indicate that the sensorimotor transformation mechanisms necessary to convert a given head velocity signal into the appropriate neck motor frame are already embedded in the networks provided by second-order vestibular neurons. Good trim of postural control will be the end result of an appropriate internal representation of the objective vertical.

Afferent Pathways↗