Zelma H. T. Kiss

Phantom sensations generated by thalamic microstimulation

Many amputees have a sense of their missing ‘phantom’ limb. Amputation can alter the representation of the bodys surface in the cerebral cortex and thalamus,, but it is unclear how these changes relate to such phantom sensations. One possibility is that, in amputees who experience phantom sensations, the region of the thalamus that originally represented the missing limb remains functional and can give rise to phantom sensations even when some thalamic ‘limb’ neurons begin to respond to stimulation of other body regions. Here we use microelectrode recording and microstimulation during functional stereotactic mapping of the ventrocaudal thalamus in amputees to determine both the responses of the neurons to stimulation of the skin and the perceptual effects of electrical activation of these neurons. Thalamic mapping revealed an unusually large thalamic stump representation, consistent with the findings from animal experiments. We also found that thalamic stimulation in amputees with a phantom limb could evoke phantom sensations, including pain, even in regions containing neurons responsive to tactile stimulation of the stump. These findings support the hypothesis that the thalamic representation of the amputated limb remains functional in amputees with phantoms.

Selective Attenuation of Afferent Synaptic Transmission as a Mechanism of Thalamic Deep Brain Stimulation-Induced Tremor Arrest

Deep brain stimulation (DBS) of the ventrolateral thalamus stops several forms of tremor. Microelectrode recordings in the human thalamus have revealed tremor cells that fire synchronous with electromyographic tremor. The efficacy of DBS likely depends on its ability to modify the activity of these tremor cells either synaptically by stopping afferent tremor signals or by directly altering the intrinsic membrane currents of the neurons. To test these possibilities, whole-cell patch-clamp recordings of ventral thalamic neurons were obtained from rat brain slices. DBS was simulated (sDBS) using extracellular constant current pulse trains (125 Hz, 60–80 μs, 0.25–5 mA, 1–30 s) applied through a bipolar electrode. Using a paired-pulse protocol, we first established that thalamocortical relay neurons receive converging input from multiple independent afferent fibers. Second, although sDBS induced homosynaptic depression of EPSPs along its own pathway, it did not alter the response from a second independent pathway. Third, in contrast to the subthalamic nucleus, sDBS in the thalamus failed to inhibit the rebound potential and the persistent Na+ current but did activate the Ih current. Finally, in eight patients undergoing thalamic DBS surgery for essential tremor, microstimulation was most effective in alleviating tremor when applied in close proximity to recorded tremor cells. However, stimulation could still suppress tremor at distances incapable of directly spreading to recorded tremor cells. These complementary data indicate that DBS may induce a “functional deafferentation” of afferent axons to thalamic tremor cells, thereby preventing tremor signal propagation in humans.

Mechanisms of deep brain stimulation: an intracellular study in rat thalamus

High‐frequency deep brain stimulation (DBS) in the thalamus alleviates most kinds of tremor, yet its mechanism of action is unknown. Studies in subthalamic nucleus and other brain sites have emphasized non‐synaptic factors. To explore the mechanism underlying thalamic DBS, we simulated DBS in vitro by applying high‐frequency (125 Hz) electrical stimulation directly into the sensorimotor thalamus of adult rat brain slices. Intracellular recordings revealed two distinct types of membrane responses, both of which were initiated with a depolarization and rapid spike firing. However, type 1 responses repolarized quickly and returned to quiescent baseline during simulated DBS whereas type 2 responses maintained the level of membrane depolarization, with or without spike firing. Individual thalamic neurones exhibited either type 1 or type 2 response but not both. In all neurones tested, simulated DBS‐evoked membrane depolarization was reversibly eliminated by tetrodotoxin, glutamate receptor antagonists, and the Ca2+ channel antagonist Cd2+. Simulated DBS also increased the excitability of thalamic cells in the presence of glutamate receptor blockade, although this non‐synaptic effect induced no spontaneous firing such as that found in subthalamic nucleus neurones. Our data suggest that high‐frequency stimulation when applied in the ventral thalamus can rapidly disrupt local synaptic function and neuronal firing thereby leading to a ‘functional deafferentation’ and/or ‘functional inactivation’. These mechanisms, driven primarily by synaptic activation, help to explain the paradox that lesions, muscimol and DBS in thalamus all effectively stop tremor.

Nursing time to program and assess deep brain stimulators in movement disorder patients.

The use of deep brain stimulation (DBS) to treat movement disorders such as Parkinsons disease, essential tremor, and dystonia is increasing. Although some published literature describes the methods for DBS programming, the time and nursing requirements to run a DBS surgical program have not been examined previously. For this study, we prospectively recorded the time required for both assessments and programming of the DBS from the preoperative period to 1 year after surgery in a variety of patients. Results showed that the mean total time spent programming the stimulator and assessing these patients ranged from 18.0-36.2 hours per patient. It took twice as long to program the stimulator in patients with Parkinsons disease as it did in patients with essential tremor or dystonia. When setting up a program for movement disorders surgery, nursing time spent on patient assessment and programming should be considered in the workload.

Smart watch accelerometry for analysis and diagnosis of tremor.

BACKGROUND Distinguishing the postural re-emergent tremor of Parkinson disease from essential tremor can be difficult clinically. Use of accelerometry to aid diagnosis is limited to laboratory settings. We sought to record and differentiate these tremors using a smart watch device in an outpatient clinic. NEW METHOD 41 patients were enrolled. Recordings were made with a smart watch device on the predominantly affected hand (all patients), and simultaneously with an analog accelerometer (10 patients) with hands at rest and outstretched. Tremor peak frequency, peak power, and power of the first four harmonics was calculated and compared between the two devices. Mean power at the first four harmonics was calculated and used to classify tremor as parkinsonian or essential. Test characteristics were calculated to compare the device and clinical diagnoses. RESULTS Mean harmonic peak power was both highly sensitive and specific for distinction of Parkinson disease postural tremor from essential tremor with an optimal threshold for our sample (sensitivity 90.9%, 95% CI 58.7-99.8%; specificity 100%, 95% CI 76.8-100%; Cohens kappa=0.91, SE=0.08). COMPARISON WITH EXISTING METHODS The smart watch and analog devices had nearly perfect concordance of peak frequency and proportional harmonic power. The smart watch recordings in clinic took 3-6 min. CONCLUSIONS A smart watch device can provide accurate and diagnostically relevant information about postural tremor. Its portability and ease of use could help translate such techniques into routine clinic use or to the community.

Plasticity in Human Somatosensory Thalamus as a Result of Deafferentation

Experimental studies indicate that deafferentation results in reorganization of the somatosensory map at various levels of the CNS, such that the representation of a body part adjacent to a region that is denervated expands into the deafferented area. Recent data suggest that in the human this occurs at the cortical level, but subcortical structures have not been systematically investigated. To test the hypothesis that the human thalamus is capable of significant reorganization as a result of changes in afferent input, microelectrode recording and stimulating techniques were used to define thalamic somatotopy in 61 patients undergoing stereotactic procedures. Five groups were compared: those with pain in the deafferented body part, face (n = 9), arm/hand (n = 4), leg/foot (n = 8) and hemibody (n = 5) and those with neither pain nor deafferentation, i.e., movement disorder (n = 24). Trunk representation, as determined from receptive fields, was significantly larger in patients with leg/foot deafferentation than in patients without deafferentation (1.8 +/- 0.7 vs. 0.5 +/- 0.2 mm; p < 0.01). Also, microstimulation induced paraesthesiae in the face from a significantly larger region of thalamus in the facially denervated group compared to the movement disorder group (13.8 +/- 2.8 vs. 3.7 +/- 0.6 mm; p < 0.001). There were no significant differences in the representation of other body parts in the five groups. The results in the leg-deafferented group agree with conclusions reached from animal studies; however, the human situation is more complex. There appear to be different patterns and degrees of somatotopic reorganization in the human, all of which may be associated with pain syndromes.

Patterns of neuronal firing in the human lateral thalamus during sleep and wakefulness

The firing patterns of thalamic neurons in mammals undergo a dramatic change as the animals state changes between sleep and wakefulness. During sleep the normal tonic firing of thalamic neurons changes into a slower bursting mode characterized by repetitive activation of a low-threshold calcium (Ca2+) current. The present report describes the patterns of thalamic neuronal firing during sleep and wakefulness in one human patient. Extracellular single neuron activity was recorded during functional stereotactic surgery in the thalamus of a patient with chronic pain, who was observed to fall asleep during the recording. Evolutive power spectra of the thalamic slow wave were used in place of cortical encephalography to confirm the patients states of sleep and wakefulness. Twenty-nine sites were observed in motor and somatosensory thalamus (Vop, Vim, and Vc) that were characterized by the presence of neurons with bursting activity when the patient was asleep. Such bursting was not observed in the patient when she was awakened. At 14 of these sites we were able to discriminate the bursting activity of single units. In each case the cell stopped firing or its bursting was replaced by a tonic firing pattern when the patient was awakened. In three cases the patient began to lapse back into sleep and the neuron resumed firing in a bursting pattern once again. None of these units had a peripheral receptive field (RF), while several other units recorded in nearby regions that did not fire in a bursting pattern during sleep had kinesthetic or cutaneous RFs. Analysis of the intraburst firing pattern revealed increasing interspike intervals (ISI) for successive action potentials in a burst and that the duration of the first ISI in the burst decreased as the number of ISIs increased. This pattern is similar to that reported to occur as a result of a calcium spike. These data have confirmed for the first time that state-dependent changes in thalamic firing exist in the human and that the physiological substrates at the thalamic level that are involved in human sleep are similar to those observed in animals.

Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is reported to be a safe and effective new treatment for treatment-resistant depression (TRD). However, the optimal electrical stimulation parameters are unknown and generally selected by trial and error. This pilot study investigated the relationship between stimulus parameters and clinical effects in SCC-DBS treatment for TRD. METHODS Four patients with TRD underwent SCC-DBS surgery. In a double-blind stimulus optimization phase, frequency and pulse widths were randomly altered weekly, and corresponding changes in mood and depression were evaluated using a visual analogue scale (VAS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17). In the open-label postoptimization phase, depressive symptoms were evaluated biweekly for 6 months to determine long-term clinical outcomes. RESULTS Longer pulse widths (270-450 μs) were associated with reductions in HAM-D-17 scores in 3 patients and maximal happy mood VAS responses in all 4 patients. Only 1 patient showed acute clinical or mood effects from changing the stimulation frequency. After 6 months of open-label therapy, 2 patients responded and 1 patient partially responded. LIMITATIONS Limitations include small sample size, weekly changes in stimulus parameters, and fixed-order and carry-forward effects. CONCLUSION Longer pulse width stimulation may have a role in stimulus optimization for SCC-DBS in TRD. Longer pulse durations produce larger apparent current spread, suggesting that we do not yet know the optimal target or stimulus parameters for this therapy. Investigations using different stimulus parameters are required before embarking on large-scale randomized sham-controlled trials.

Behavioral effects of subthalamic deep brain stimulation in Parkinson's disease

To date, few studies have utilized standardized measures to assess the neurobehavioral changes that can accompany deep brain stimulation (DBS) of the subthalamic nuclei (STN) for the treatment of Parkinsons disease (PD), yet behavioral changes are the most debated among practitioners. We evaluated behavior with the Frontal Systems Behavior Scale (FrSBe), which includes a large-scale normative sample for self- and collateral ratings and is particularly relevant to PD with subscales assessing Apathy, Disinhibition, and Executive Dysfunction. Data were collected from 16 (11 males) PD patients. All FrSBe subscale scores increased significantly when retrospective preoperative scores and current (postoperative) scores were compared. Self- and collateral FrSBe ratings were not significantly correlated with each other, though for both scores at least half of the group met criteria for a clinically significant level of symptoms postoperatively. No significant correlations were seen for collateral current FrSBE ratings with cognitive or motor variables. Higher self-ratings of behavior characteristic of apathy were related to higher self-ratings of depressive symptoms, and to a smaller decrease in antiparkinsonian medications following surgery. We propose that the standardized assessment of behavioral aspects of executive dysfunction adds information that is largely dissociable from the motor and cognitive assessment of function in PD patients undergoing STN DBS. In future, prospective standardized measurement of behavior may allow for better prediction of which patients will experience significant behavioral issues postoperatively.

Both thalamic and pallidal deep brain stimulation for myoclonic dystonia

Myoclonic dystonia is poorly managed with medication and may be severe enough to warrant surgical intervention. Surgery has targeted either the globus pallidus pars interna (GPi) or the thalamus, but there is no accepted target for this condition. The authors present the case of a 23-year-old man treated with unilateral deep brain stimulation in both the thalamus and GPi. His movement disorder improved dramatically with stimulation. Two years postoperatively, the authors performed a double-blind assessment of the effects of each stimulator together, separately, and off stimulation. Videotape assessment, using tremor, dystonia, and myoclonus rating scales, showed that most of the benefit could be attributed to pallidal stimulation, although there was some advantage to stimulation at both sites. These results suggest that while GPi stimulation may be the better target for this condition, thalamic stimulation may be added in cases in which the benefit is insufficient.