Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation.

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy.

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.

Delta opioid receptor mRNA expression is changed in the thalamus and brainstem of monoarthritic rats.

Changes in the mRNA expression of neurotransmitters receptors under chronic pain conditions have been described in various areas of the central nervous system (CNS). Delta opioid receptors (DORs) have been implicated in pain mechanisms but, although its mRNA expression has been studied in the rat CNS, there are no reports describing its distribution in specific thalamic and brainstem nuclei during chronic inflammatory pain. Here, in situ hybridization for DOR mRNA was performed in brain sections from control and monoarthritic (MA) rats with 2, 4, 7 and 14 days of inflammation. Grain densities were determined bilaterally in the ventrobasal complex (VB), posterior (Po), centromedial/centrolateral (CM/CL) and reticular (Rt) nuclei of the thalamus, and in the dorsal reticular (DRt), lateral reticular (LRt) and parvocellular reticular (PCRt) nuclei of the brainstem. Control animals exhibited weak mRNA expression in the VB, Po and CM/CL, as well as in PCRt, while moderate grain densities were observed in the Rt, DRt and LRt. During MA, DOR mRNA expression was significantly decreased (22%) in the Rt contralateral to the affected joint at both 7 and 14 days of inflammation, as compared to controls. A bilateral reduction (35%) was also observed in the DRt at 14 days of MA, while a contralateral increase was found in the PCRt at 7 days (+39%). No significant changes were observed in the other regions analyzed. Thus, data show changes in the DOR mRNA expression during the development of chronic inflammatory pain, in thalamic and brainstem nuclei implicated in pain processing mechanisms.

Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus.

Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABAB) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABAB receptors on GABAergic projections to PO-characteristic of normal animals-was absent in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABAB receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments. PERSPECTIVE: This report presents synaptic mechanisms that may underlie the development and maintenance of SCI-Pain. Because of the difficulty in treating SCI-Pain, a better understanding of the underlying neurobiological mechanisms is critical, and may allow development of better treatment modalities.

Blood flow disturbance in perforating arteries attributable to aneurysm surgery.

OBJECT: The object of this study was to investigate patients with cerebral infarction in the area of the perforating arteries after aneurysm surgery. METHODS: The authors studied the incidence of cerebral infarction in 1043 patients using computed tomography or magnetic resonance imaging and the affected perforating arteries, clinical symptoms, prognosis, and operative maneuvers resulting in blood flow disturbance. RESULTS: Among 46 patients (4.4%) with infarction, the affected perforating arteries were the anterior choroidal artery (AChA) in nine patients, lenticulostriate artery (LSA) in nine patients, hypothalamic artery in two patients, posterior thalamoperforating artery in five patients, perforating artery of the vertebral artery (VA) in three patients, anterior thalamoperforating artery in nine patients, and recurrent artery of Heubner in nine patients. Sequelae persisted in 21 (45.7%) of the 46 patients; 13 (28.3%) had transient symptoms and 12 (26.1%) were asymptomatic. Sequelae developed in all patients with infarctions in perforating arteries in the area of the AChA, hypothalamic artery, or perforating artery of the VA; in four of five patients with posterior thalamoperforating artery involvement; and in two of nine with LSA involvement. The symptoms of anterior thalamoperforating artery infarction or recurrent artery of Heubner infarction were mild and/or transient. The operative maneuvers leading to blood flow disturbance in perforating arteries were aneurysmal neck clipping in 21 patients, temporary occlusion of the parent artery in nine patients, direct injury in seven patients, retraction in five patients, and trapping of the parent artery in four patients. CONCLUSIONS: The patency of the perforating artery cannot be determined by intraoperative microscopic inspection. Intraoperative motor evoked potential monitoring contributed to the detection of blood flow disturbance in the territory of the AChA and LSA.

GABA(B2) receptor subunit mRNA decreases in the thalamus of monoarthritic animals.

Many studies have implicated GABA(B) receptors in pain transmission mechanisms, especially in the spinal cord. In the thalamus, mRNA expression of the GABA(B(1b)) isoform was shown to be regulated in relay nuclei in response to chronic noxious input arising from experimental monoarthritis. GABA(B(1a)) and GABA(B2) mRNA expression was here determined by in situ hybridisation in the brain of control, 2, 4, 7 and 14 days monoarthritic rats, to evaluate whether this expression was regulated by chronic noxious input in thalamic nuclei. mRNA labelling was analysed quantitatively in the ventrobasal complex, posterior, central medial/central lateral and reticular thalamic nuclei; the thalamic visual relay and dentate gyrus were examined for control. No mRNA expression was detected for GABA(B(1a)) in control and monoarthritic animals. Similarly, GABA(B2) mRNA was not found in the reticular nucleus. However, GABA(B2) mRNA expression was observed in the ventrobasal complex, posterior and central medial/central lateral nuclei of control animals. A significant decrease of 42% at 2 days and 27% at 4 days of monoarthritis was observed in the ventrobasal complex contralaterally, when compared with controls, returning to basal levels at 7 days of monoarthritis. In the ipsilateral posterior nucleus, there was a significant decrease of 38% at 2 days of monoarthritis. No significant changes were observed in central medial/central lateral nuclei. The data suggest that GABA(B2) mRNA expression in the ventrobasal complex and posterior nucleus is regulated by noxious input and that GABA(B) receptors might play a role in the plasticity of these relay nuclei during chronic inflammatory pain.

Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury.

Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. Behavioural testing with von Frey hairs established that 11 spinally injured rats showed exaggerated vocal responses to normally innocuous mechanical stimulation (allodynia) whereas eight were non-allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non-allodynic) exhibited a dysrhythmia in that a significantly higher proportion fired spontaneously in an oscillatory mode when compared with neurones in uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to allodynia. The evoked responses of VPL thalamic neurones to brushing the skin, however, were significantly elevated in allodynic rats when compared with those in uninjured rats and neuronal afterdischarges to these stimuli (which were absent in uninjured rats) were more common in allodynic than in non-allodynic rats. We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury.

Subthalamic prelemniscal radiation stimulation for the treatment of Parkinson's disease: electrophysiological characterization of the area.

Previous reports have provided evidence of a reticulo-thalamic system, extending from the mesencephalic reticular formation (MRF) to the ventrolateral thalamus (VL), involved in the production of tremor. In humans, a funnel of fibers in the posterior subthalamus named the prelemniscal radiations (Raprl) has been described as an exquisite target to treat tremor in cases of Parkinson's disease. In the present study, a group of 14 patients suffering from Parkinson's disease, with prominent unilateral tremor and rigidity, were implanted with tetrapolar depth brain stimulation (DBS) electrodes in Raprl to perform chronic electrical stimulation (ES) for the treatment of patient symptoms. Electrodes were left externalized to corroborate their placement throughout MRI studies and also to perform the following electrophysiological battery: (a) recording of somatosensory-evoked responses (SEP) through different electrode contacts and scalp by means of a paradigm to study the attention process; (b) evoking scalp EEG responses by stimulation with low (3 cps, 6 cps) and high (60-120 cps) frequencies with stimuli delivered through different electrode contacts, and (c) studying recovery cycle (RC) potentials in the Raprl while the upper MRF was being stimulated and, conversely, the RC in MRF while Raprl was being stimulated, before and after subacute Raprl stimulation. Thereafter, the electrodes were internalized and connected to a pulse generator (IPG) to carry on chronic ES, while the effects of stimulation were determined through a quantitative evaluation that measured phasic and tonic muscular activity with EMG recordings during different motor tasks. Results indicate the following: (a) that late, but not early, SEP components were recorded in Raprl and modulated in different attentive conditions; (b) that bilateral recruiting responses and spike and wave complexes were elicited by Raprl through low-frequency stimulation, while bilateral positive DC shifts induced by high-frequency stimulation were recorded, similar to those obtained in animals from MRF, and (c) that Raprl-ES induced RC inhibition at Raprl, but Raprl ES did not change MRF-RC. Long-term Raprl-ES induced a significant decrease in tremor and rigidity. It was concluded that Raprl represents a subthalamic circuit electrophysiologically related to MRF in the genesis of tremor and rigidity and in the process of selective attention. Raprl-ES induced a significant improvement in tremor and rigidity by causing inhibition of the stimulated area.

Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion.

Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

Chronic stress induces dendritic atrophy in the rat medial geniculate nucleus: effects on auditory conditioning.

Chronic stress induces dendritic atrophy in the inferior colliculus (IC, auditory mesencephalon) and impairs auditory avoidance conditioning. The aim of this study was to determine in Golgi preparations and in cued fear conditioning whether stress affects other auditory components, like the thalamic medial geniculate nucleus (MG) or the posterior thalamic nucleus (PO), in Sprague-Dawley rats. Chronic restraint stress produced a significant dendritic atrophy in the MG (stress: 407+/-55 microm; control: 808+/-120 microm; p<0.01) but did not affect auditory fear conditioning. The last result was in apparent contrast with the fact that stress impairs both the acquisition of auditory avoidance conditioned responses and the dendritic structure in two major nuclei of the auditory system. In order to analyze this disagreement, we investigated whether the stress-related freezing to tone occurring in the fear conditioning protocol corresponded to a conditioned or an unconditioned fear response, using changes in tone instead of light throughout conditioning trials. Chronic stress significantly enhanced visual fear conditioning in stressed animals compared to controls (stress: 58.9+/-8.42%, control: 23.31+/-8.01%; p<0.05), but this fear enhancement was related to unconditioned fear. Conversely, chronic stress did not affect the morphology of the PO (subserving both auditory and somatosensory information) or the corresponding auditory and somatosensory unconditioned responses (acoustic startle response and escape behavior). Our results suggest that the auditory conditioned stimulus can be processed in part independently of the IC and MG in the stressed animals, and sent to the amygdala via the PO inducing unconditioned fear. Comparable alterations could be produced in major depression.

Posterior thalamic hemorrhage induces "pusher syndrome".

BACKGROUND: Recent findings argue for a pathway in humans for sensing the orientation of gravity and controlling upright body posture, separate from the one for orientation perception of the visual world. Stroke patients with contraversive pushing were shown to experience their body as oriented upright when actually tilted about 20 degrees to the ipsilesional side, in spite of normal visual-vestibular functioning. A recent study suggested the involvement of posterolateral thalamus typically associated with the disorder. OBJECTIVE: To evaluate the relationship between pushing behavior and thalamic function. METHODS: Over a 3-year period the authors prospectively investigated 40 patients with left- or right-sided thalamic strokes. RESULTS: Twenty-eight percent showed contraversive pushing. The authors found a strong relationship between etiology, vascular territory, lesion size, and neurologic disorders associated with contraversive pushing. Pusher patients had larger lesions that typically were caused by hemorrhage (vs infarcts) located in the posterior thalamus (vs anterior thalamic lesions in those patients without pushing behavior). A paresis of the contralesional extremities was more frequent and more severe in pusher patients. Further, these patients showed more additional spatial neglect with right thalamic lesions, while they tended to be more aphasic with left thalamic lesions. CONCLUSIONS: Posterior thalamus seems to be fundamentally involved in our control of upright body posture. Higher pressure, swelling, and other secondary pathologic processes associated with posterior thalamic hemorrhage (vs thalamic infarction) may provoke contraversive pushing in combination with additional neurologic symptoms.

Effects of lesions of the human posterior thalamus on ocular fixation during voluntary and visually triggered saccades.

OBJECTIVE: To investigate the role of the posterior thalamus in controlling voluntary and visually triggered eye movements and ocular fixation. METHODS: The latency to initiate saccades to peripheral targets (visually triggered) and in response to verbal commands (voluntary) was measured in three patients with unilateral lesions of the posterior thalamus, in normal controls, and in neurological controls with Parkinson's disease. On half the trials a fixation point offset simultaneously with target onset, and on half it remained visible. RESULTS: Offset of the fixation point simultaneous with target onset decreased saccade latency for both voluntary and visually triggered eye movements in controls, but only for voluntary saccades in patients with thalamic lesions. CONCLUSIONS: These findings suggest that separate neural systems control fixation when making voluntary and visually triggered eye movements, and that the thalamus is involved in the control of fixation for visually triggered but not for voluntary saccades.

A combined pattern of movement disorders resulting from posterolateral thalamic lesions of a vascular nature: a syndrome with clinico-radiologic correlation.

We report a series of seven patients in whom a combined pattern of complex movement disorders restricted to one upper extremity emerged as a result of posterolateral thalamic lesions of vascular origin. This disorder was mainly characterized by choreiform and dystonic movements associated with variable, rhythmic, alternating movements of low frequency (myorhythmia). All cases showed, on computed tomography scan and/or magnetic resonance imaging, focal lesions involving the posterolateral quadrant of the thalamus. Review of similar cases reported with identical clinico-radiologic features allows us to conclude that it is possible to establish an accurate anatomoclinical correlation based on the clinical phenomenology, even before imaging studies are performed, in these cases. The opposite is not entirely possible, however, because lesions in the same quadrant of the thalamus are often associated with different patterns of abnormal movements or present without abnormal movements.

Primary somatosensory cortex activation is not altered in patients with ventroposterior thalamic lesions: a PET study.

BACKGROUND AND PURPOSE: We know remarkably little about the mechanisms underlying cortical activation. Such mechanisms might be better understood by studying the effect of well-localized lesions on the cortical activations in simple paradigms. METHODS: We used H(2)(15)O and positron emission tomography to measure regional cerebral blood flow (rCBF) at rest and during hand vibration in 7 patients with unilateral thalamic lesion involving the ventroposterior (VP) somatosensory thalamic relay nuclei. We compared the results with those obtained in 6 patients with thalamic lesions sparing the VP nuclei and 6 healthy controls. RESULTS: The patients with VP lesions had a selective hypoperfusion at rest in the ipsilesional primary sensorimotor cortex (SM1). This hypoperfusion was significantly correlated with the degree of contralateral somatosensory deficit. This abnormality may reflect the deafferentation of SM1 from its somatosensory thalamic input. Despite this deafferentation, the ipsilesional SM1 was normally activated by the vibration of the hypoesthetic hand. CONCLUSIONS: The fact that a lesion of the somatosensory thalamic relay nuclei alters the rCBF at rest in SM1 but not its activation by hand vibration indicates that the mechanism of cortical activation is complex, even in the case of simple sensory stimulation. In addition, a dissociation may occur between obvious neurological deficits and apparently normal activation patterns, which suggests that activation studies should be interpreted cautiously in patients with focal brain lesions.