Injury of the dentato-rubro-thalamic tract in a patient with intentional tremor after mild traumatic brain injury: a case report.

OBJECTIVES: We imaged the dentato-rubro-thalamic tract (DRTT) and cortico-ponto-cerebellar tract (CPCT) using diffusion tensor tractography (DTT) to evaluate the cortico-cerebellar-cortical circuit in a patient with tremor in both hands after mild TBI. We found bilateral DRTT injury in the DTT. METHOD: A 50-year-old male presented with action tremor in both hands 1 week after mild TBI. One month before the visit, the patient had a head injury from a fall on a bus. The patient lost consciousness for 1 min and experienced post-traumatic amnesia for approximately 5 min after the accident. His Glasgow Coma Scale score was 15. The action tremor presented with a frequency of 3 Hz in both hands. No specific lesion was observed with a conventional brain MRI. RESULTS: DTT, performed 1.5 months after TBI, showed that the right DRTT was not reconstructed and the left DRTT had thinned. However, CPCT integrity was well-preserved in both hemispheres. The tremor disappeared after oral treatment with 30 mg/day indenol. The patient's tremor would have been caused by disruption of the bilateral DRTT following mild TBI. CONCLUSION: DRTT and CPCT analysis using DTT would be useful for diagnosing abnormal movement problems, including tremor and ataxia, in patients following mild TBI.

Aggravation of an injured dentato-rubro-thalamic tract in a patient with mild traumatic brain injury: A case report.

RATIONALE: We report on a patient with mild traumatic brain injury (TBI) by follow-up diffusion tensor tractography (DTT), and observed for approximately nine monthsby serial diffusion tensor tractography (DTT). PATIENT CONCERNS: A 66-year-old male patient was injured in a car crash. Approximately four weeks after the crash, he developed a tremor in the right hand and leg. His symptoms worsened over time. DIAGNOSES: Approximately six months after the crash, he developed a mild tremor in the left hand. Nine months after the crash, he manifested severe tremor in his right hand, mild resting and intentional tremor in his left hand and both legs, and mild trunkal ataxia. INTERVENTIONS: N/A. OUTCOMES: On 3-week DTT, well reconstructed DRTTs were observed in both hemispheres, except for the thinned lower portion of the right DRTT. On 9-month DTT, the right lower DRTT had thinned compared with the 3-week DTT and showed a disruption at the upper portion. The left DRTT showed thinning in the lower portion and tearing in the upper portion compared with 3-week DTT. LESSONS: Aggravation of an injured DRTT was demonstrated in a patient with mild TBI, using serial DTT examination.

Injury of the dentato-rubro-thalamic tract in a patient with mild traumatic brain injury.

BACKGROUND: Several studies using diffusion tensor tractography (DTT) have demonstrated injury of the dentato-rubro-thalamic tract (DRTT) in various brain pathologies. However, no study on traumatic brain injury (TBI) has been reported. This case study attempted to demonstrate injury of the DRTT in a patient with mild TBI, using DTT. CASE DESCRIPTION: A 41-year-old female patient suffered from head trauma resulting from flexion-hyperextension injury by being hit from behind by a running car while stopped at an intersection. The patient lost consciousness and experienced post-traumatic amnesia for ∼1minute from the time of the car-accident. The patient's Glasgow Coma Scale score was 15. No specific lesion was observed on brain MRI. At 2 weeks after onset, the patient began to show resting and intentional tremor (more severe in the right upper and lower extremities) and ataxic gait. Her symptoms had been aggravated with the passage of time. On 1-month DTT, the left DRTT, which originated from the left dentate nucleus of the cerebellum, was thinner than the right DRTT. CONCLUSIONS: This study demonstrated injury of the DRTT in a patient with tremor and ataxia following mild TBI, using DTT. It is believed that analysis of the DRTT using DTT would be useful in elucidating the cause of post-traumatic abnormal movements.

Direct visualization of cerebellar nuclei in patients with focal cerebellar lesions and its application for lesion-symptom mapping.

As yet, human cerebellar lesion studies have not taken advantage of direct magnetic resonance imaging (MRI) of the cerebellar nuclei in individual patients. In the present study, susceptibility weighted imaging (SWI) was used to visualize lesions of the dentate nuclei in patients with chronic focal lesions. Fifteen patients with cerebellar lesions either due to stroke or tumor surgery underwent SWI imaging using a 1.5T MRI scanner. Dentate nuclei were seen as hypointensities in all patients. Three of the patients underwent additional SWI imaging at 3T and 7T. Compared to 1.5T, corrugation of the dentate wall was seen with greater precision and the dorsal, iron-poorer part was seen more fully. Lesion-symptom mapping was performed based on the 1.5T MR images. Patients were divided into two groups with and without upper limb ataxia. A region-of-interest-(ROI)-driven normalization technique was used which had initially been developed by Diedrichsen et al. (2011) for functional MRI (fMRI) of the dentate nuclei. Compared to conventional normalization of the cerebellum, overlap of dentate lesions improved and lead to increased sensitivity of lesion-symptom maps. Subtraction analysis revealed that the more dorsal and rostral parts of the dentate nuclei were related to upper limb ataxia. Findings were in good accordance with the dentate hand area shown in recent fMRI studies. These data provide evidence that direct identification of dentate lesions together with the ROI-driven normalization technique allows for improved lesion-symptom mapping at the level of the cerebellar nuclei already at conventional 1.5T MRI field strength.

Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination.

Correct neural function depends on precisely organized connectivity, which is refined from broader projections through synaptic/collateral elimination. In the rat, olivocerebellar topography is refined by regression of multiple climbing fiber (CF) innervation of Purkinje cells (PC) during the first two postnatal weeks. The molecules that initiate this regression are not fully understood. We assessed the role of cerebellar neurotrophins by examining tropomycin receptor kinase (Trk) receptor expression in the inferior olive and cerebellum between postnatal days (P)3-7, when CF-PC innervation changes from synapse formation to selective synapse elimination, and in a denervation-reinnervation model when synaptogenesis is delayed. Trks A, B, and C are expressed in olivary neurons; although TrkA was not transported to the cerebellum and TrkC was unchanged during innervation and reinnervation, suggesting that neither receptor is involved in CF-PC synaptogenesis. In contrast, both total and truncated TrkB (TrkB.T) increased in the olive and cerebellum from P4, whereas full-length and activated phosphorylated TrkB (phospho-TrkB) decreased from P4-5. This reveals less TrkB signaling at the onset of CF regression. This expression pattern was reproduced during CF-PC reinnervation: in the denervated hemicerebellum phospho-TrkB decreased as CF terminals degenerated, then increased in parallel with the delayed neosynaptogenesis as new CFs reinnervated the denervated hemicerebellum. In the absence of this signaling, CF reinnervation did not develop. Our data reveal that olivocerebellar TrkB activity parallels CF-PC synaptic formation and stabilization and is required for neosynaptogenesis. Furthermore, TrkB.T expression rises to reduce TrkB signaling and permit synapse elimination.

Injuries to inferior vermis and dentate nuclei predict poor neurological and neuropsychological outcome in children with malignant posterior fossa tumors.

BACKGROUND: Children treated for a malignant posterior fossa tumor (PFT) are at risk of intellectual impairment. Its severity is not explained by age and radiotherapy alone. The current study was designed to define the correlations between the anatomical damage and the neurological/neuropsychological deficits in children with a malignant PFT. METHODS: Sixty-one consecutive children (mean age, 6.0 years) treated for a malignant PFT with surgery, chemotherapy, and radiotherapy underwent a detailed neuropsychological evaluation, including a full-scale intelligence quotient (FSIQ), on average 5.6 years after the diagnosis. The neurological examination was recorded 1 month after surgery and at the time of the neuropsychological evaluation. Cerebellar and brain injuries were scored based on the magnetic resonance imaging (MRI). Correlation of these injuries with neurological and cognitive outcome were performed after adjustment for other potential risk factors (radiotherapy schedule, age, hydrocephalus, duration of symptoms, socioeconomic status, and surgical complications). RESULTS: Neurological deficits were strong predictors of low cognitive performances irrespective of the other risk factors. The extent of cerebellar deficits and fine motor dexterity impairment were correlated with the degree of damage to the dentate nuclei and inferior vermis. The IQ scores were inversely correlated with the severity of the damage to the dentate nuclei; mean FSIQ was 83 if they were both intact and 65 in the case of bilateral damage (P=.009). CONCLUSIONS: Damage to the dentate nuclei and to the inferior vermis, observed on MRI, predict the degree of impairment of neurological and neuropsychological functions in children treated for a malignant PFT.

[Involvement of cerebellohypothalamic projections in the modulation of lymphocyte function by cerebellar fastigial nuclei].

AIM: To explore the effect of cerebellar fastigial nuclei (FN)on lymphocyte function and the pathway mediating the effect. METHODS: Kainic acid (KA) was microinjected into bilateral FN of rats to destroy neuronal bodies in the FN. On the eighth day after the surgery, lymphocyte percentage in the peripheral blood and level of sheep red blood cell(SRBC)-specific IgM antibody in the serum were measured by using blood corpuscle counter and enzyme-linked immunosorbent assay (ELISA), respectively.A technology of electrolytic lesion was used to destroy the projections of cerebellar FN neurons to hypothalamus in decussation of superior cerebellar peduncle(xscp). RESULTS: On the eighth day after the microinjection of KA into the bilateral FN of rats, the Nissl-stained neuronal bodies in the FN disappeared and glia could proliferated within the damaged FN. In the nuclei close to FN, the interposed nuclei and the dentate nuclei, Nissl-stained neurons still could be seen. On the control cerebellar sections, in which FN was infused with saline, we could see the normal Nissl-stained neurons in the FN and the other two nuclei.On day 8 following the effective FN lesions, both the lymphocyte percentage in the peripheral blood and the level of anti-SRBC IgM antibody in the serum were significantly increased in comparison with those of control rats infused with saline in the FN. On the eighth day after electrolytic lesion of the fibres in xscp, the FN-hypothalamic projections were damaged and there were no visible BDA-positive endings in hypothalamus. Meanwhile, both the lymphocyte percentage in the peripheral blood and the level of anti-SRBC IgM antibody in the serum were remarkably enhanced relative to those of control rats with sham lesion of xscp. CONCLUSION: The electrolytic lesion of the FN-hypothalamic projections in xscp causes an enhancement of lymphocyte function similar to that of KA lesions of neuronal soma in the FN. These findings suggest that the cerebellohypothalamic projections participate in mediating the modulation of lymphocyte function by the cerebellum.

Transient cerebellar mutism caused by bilateral damage to the dentate nuclei after the second posterior fossa surgery. Case report.

The authors report on the case of a 6-year-old boy who underwent resection of a midline cerebellar tumor. The boy was able to speak fluently after the operation. Magnetic resonance (MR) imaging showed that the right dentate nucleus had been partially removed along with the tumor, but that the left dentate nucleus remained with the residual tumor. A second operation was performed to remove the residue, after which the child suffered mutism. Three weeks post-surgery, he could only communicate through gestures. He started speaking I week later and regained normal speech 2 months after the operation. Final MR imaging revealed gross-total removal of the tumor and dentate nucleus on the injured left side. The cerebellar mutism was considered to have been caused by bilateral damage to the dentate nuclei and not by unilateral damage.

Effect of lesions of cerebellar fastigial nuclei on lymphocyte functions of rats.

The cerebellum, probably owing to its traditional concept limited to motor control, is less well studied in immunoregulation. To obtain more comprehension and knowledge on cerebellar functions, we investigated effect of cerebellar fastigial nucleus (FN), an output nucleus of the spinocerebellum, on lymphocyte functions, and explored central and peripheral pathways involved in the effect. Kainic acid (KA) was microinjected into bilateral FN of rats (0.4 microg KA in 0.4 microl saline for each side) to destroy neurons of the nuclei. On days 8, 16 and 32 following the FN lesions, methyl-thiazole-tetrazolium (MTT) assay and flow cytometry were used to measure proliferation of concanavalin A (Con A)-induced lymphocytes and cytotoxicity of natural killer (NK) cells against YAC-1 cells, respectively. Meanwhile, glutamate and monoamine neurotransmitters, including norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT), in the hypothalamus and the spleen were determined by means of high-performance liquid chromatography (HPLC) assay. Adrenocorticotropic hormone (ACTH) and cortisol in the plasma were also detected respectively by radioimmunoassay and chemiluminescent immunoassay after the FN lesions. We found that the Con A-induced lymphocyte proliferation and the NK cell cytotoxicity were both significantly enhanced on days 8, 16 and 32 following the effective lesions of the bilateral FN in comparison with those of matching control rats microinjected with saline in their FN. Contents of glutamate and NE, not DA and 5-HT, in the hypothalamus, and concentration of NE, not DA, in the spleen were all remarkably reduced on the 16th day following the FN lesions, when both the T lymphocyte proliferation and the NK cell cytotoxicity were dramatically increased. However, levels of ACTH and cortisol in the plasma had no notable differences between FN lesion rats and FN saline ones when the enhanced T and NK cell functions occurred. These findings reveal that the cerebellar FN participates in the modulation of lymphocyte functions and that the hypothalamus and sympathetic nerves innervating lymphoid organs are involved in this neuroimmunomodulation. Thus, a possible central and peripheral pathway for the spinocerebellum to regulate lymphocyte functions is suggested, i.e. cerebellum-hypothalamus-sympathetic nerves-lymphocytes, while the functional axis of hypothalamus-pituitary-adrenal gland may not contribute to mediation of the spinocerebellar immunomodulation.

Ocular oscillations generated by coupling of brainstem excitatory and inhibitory saccadic burst neurons.

The human saccadic system is potentially unstable and may oscillate if the burst neurons, which generate saccades, are not inhibited by omnipause neurons. A previous study showed that combined saccade vergence movements can evoke oscillations in normal subjects. We set out to determine: 1) whether similar oscillations can be recorded during other paradigms associated with inhibition of omnipause neurons; 2) whether lesions of the fastigial nuclei disrupt such oscillations; and 3) whether such oscillations can be reproduced using a model based on the coupling of excitatory and inhibitory burst neurons. We recorded saccadic oscillations during vergence movements, combined saccade-vergence movements, vertical saccades, pure vergence and blinks in three normal subjects, and in a patient with saccadic hypermetria due to a surgical lesion affecting both fastigial nuclei. During combined saccade-vergence, normal subjects and the cerebellar patient developed small-amplitude (0.1 - 0.5 degrees), high-frequency (27-35 Hz), conjugate horizontal saccadic oscillations. Oscillations of a similar amplitude and frequency occurred during blinks, pure vergence and vertical saccades. One normal subject could generate saccadic oscillations voluntarily (approximately 0.7 degrees amplitude, 25 Hz) during sustained convergence. Previous models proposed that high-frequency eye oscillations produced by the saccadic system (saccadic oscillations), occur because of a delay in a negative feedback loop around high-gain, excitatory burst neurons in the brainstem. The feedback included the cerebellar fastigial nuclei. We propose another model that accounts for saccadic oscillations based on 1) coupling of excitatory and inhibitory burst neurons in the brainstem and 2) the hypothesis that burst neurons show post-inhibitory rebound discharge. When omnipause neurons are inhibited (as during saccades, saccade-vergence movements and blinks), this new model simulates oscillations with amplitudes and frequencies comparable to those in normal human subjects. The finding of saccadic oscillations in the cerebellar patient is compatible with the new model but not with the recent models including the fastigial nuclei in the classic negative-feedback loop model. Our model proposes a novel mechanism for generating oscillations in the oculomotor system and perhaps in other motor systems too.

Evidence for a role of dopaminergic mechanisms in the immunostimulating effect of mu-opioid receptor agonist DAGO.

The present study demonstrates that: (1) activation of micro -opioid receptors by systemic administration of a highly selective agonist DAGO (100 microg/kg) results in a significant increase in the number of plaque- and rosette-forming cells in the spleen of CBA mice as well as Wistar rats on the 5th day following sheep red blood cells (5 x 10(8)) immunization, (2) the immunostimulatory effect of DAGO is mediated by central mechanisms including the hypothalamus-hypophysis complex; (3) the postsynaptic dopamine (DA) receptors of D2 type are involved in the DAGO-induced immunostimulation since the combined treatment of animals with haloperidol (2 mg/kg), a blocker of DA D2 receptors, and DAGO abolished this effect; (4) the nuclei caudatus and accumbens of the nigrostriatal and mesolimbic DAergic systems, respectively, are implicated in the immune response stimulation caused by DAGO.

Altered visuo-motor behavior during inactivation of the caudal fastigial nucleus in the cat.

It is known that the medio-posterior cerebellar lobules VI/VII of the vermis and caudal part of the fastigial nucleus (cFN) are involved in the control of saccadic displacements of the visual axis in space (gaze). We have recently shown in the head-unrestrained cat that inactivation of the cFN severely impairs the accuracy of orienting gaze shifts toward visual targets by altering the amplitude of both eye and head components. In the present paper, we report additional data that indicate that the deficits induced by cFN inactivation are not restricted to saccadic gaze shifts but extend to the forward reaching movement of the whole body toward a visual target. Indeed, the path followed by the animal walking toward a visible food target was systematically curved toward the inactivated side. This deficit could largely be accounted for by an angular bias in the heading direction used by the animal to reach the target. These data suggest that pharmacological inactivation of the cFN leads to a general deficit in spatial orientation.

An electron microscopic study of the corticorubral fibers after neonatal deep cerebellar nuclear lesions in albino rats.

After a lesion in the sensorimotor and adjacent cortex in normal adult rats, degenerating terminals showing the dense reaction form asymmetrical contacts with spines, dendrites of various sizes, soma and other axonal terminals. Filamentous degeneration is also present. After neonatal deep cerebellar nuclear lesions involving the dentate nucleus and the adjacent interposed nucleus, the cerebrocorticorubral fibers form similar synaptic contacts with somatic, dendritic and axonal profiles. The incidence of axo-dendritic contacts on spine is reduced, while that of axo-dendritic contacts on small, medium-sized and large dendrites and axo-somatic contacts is increased.

Recovery of locomotor function in cats after localized cerebellar lesions.

Cats were trained to walk on a motorized treadmill, at speeds up to a brisk walk, for food reward. A cerebellar lesion was placed in each animal, either unilateral removal of paravermal cortex, or unilateral coagulation of n. interpositus, or bilateral coagulation of the fastigial nuclei. The effects of these lesions upon locomotor activity were measured by conventional kinematic methods, and were found to be generally in agreement with prior observations. Also in agreement with prior work was the fact that these initial deficits disappeared in a relatively short time. The kinematic data suggest that this recovery of function was genuine in the sense that compensatory alterations in limb motion could not be demonstrated. In disagreement with prior studies, we failed to elicit decompensation (e.g. reinstatement of the original deficits) by subsequent pyramidal tract sections, or ablation of the 'motor' cortex. We conclude that the corticospinal system is probably not essential to the recovery observed, and also that perhaps there are substantial differences in the mechanisms of recovery of 'spontaneous' overground locomotion, compared to walking on a treadmill as a conditioned instrumental response.

Characteristics of nystagmus produced by reversible lesions of the medial cerebellar nuclei in the alert monkey.

Synaptic activity of the medial cerebellar nuclei was reversibly blocked in 6 Cebus monkeys by cooling through a sheath implanted alongside the fastigial nucleus. Such lesions produced in the dark a strong nystagmus (slow phase velocity 100-200 deg/sec). The slow phase of nystagmus was predominantly in the horizontal plane and was towards the side of the lesion (ipsilateral drift). The maximum velocity of drift was independent of eye position and was directly related to the degree of cooling. Vision abolished the nystagmus. If lights were turned on during nystagmus the drift velocity rapidly decreased to zero with an instantaneous and an exponential component. It is suggested that these results emphasize the importance of the medial cerebellum, possibly by way of the fastigial nucleus, in balancing the output of the paired vestibular nuclei.

Projections of the superior cerebellar peduncle in rats and the development of new connections in response to neonatal hemicerebellectomy.

The normal distribution pattern of cerebellar efferents was determined using the Fink-Heimer technique in adult rats that sustained stereotaxic transection of the superior cerebellar peduncle. This pattern was found to be essentially similar to earlier studies and corroborated more recent reports of projections to the pontine gray and inferior olivary nuclei. Comparisons were made to a second group of animals that underwent neonatal hemicerebellectomy in addition to adult transection of the contralateral superior cerebellar peduncle. Abnormal projections to the ipsilateral red nucleus and ventral thalamus were observed in addition to evidence suggestive of axonal sprouting within the oculomotor complex. These animals also demonstrated an absence of cells in the pontine gray and inferior olive on the side contralateral to the hemicerebellectomy and in the lateral reticular and lateral cuneate nuclei on the ipsilateral side.