Human thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning.

Reinforcement-based adaptive decision-making is believed to recruit fronto-striatal circuits. A critical node of the fronto-striatal circuit is the thalamus. However, direct evidence of its involvement in human reinforcement learning is lacking. We address this gap by analyzing intra-thalamic electrophysiological recordings from eight participants while they performed a reinforcement learning task. We found that in both the anterior thalamus (ATN) and dorsomedial thalamus (DMTN), low frequency oscillations (LFO, 4-12 Hz) correlated positively with expected value estimated from computational modeling during reward-based learning (after outcome delivery) or punishment-based learning (during the choice process). Furthermore, LFO recorded from ATN/DMTN were also negatively correlated with outcomes so that both components of reward prediction errors were signaled in the human thalamus. The observed differences in the prediction signals between rewarding and punishing conditions shed light on the neural mechanisms underlying action inhibition in punishment avoidance learning. Our results provide insight into the role of thalamus in reinforcement-based decision-making in humans.

Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields.

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

The Ictal Signature of Thalamus and Basal Ganglia in Focal Epilepsy: A SEEG Study.

OBJECTIVE: To determine the involvement of subcortical regions in human epilepsy by analyzing direct recordings from these regions during epileptic seizures using stereo-EEG (SEEG). METHODS: We studied the SEEG recordings of a large series of patients (74 patients, 157 seizures) with an electrode sampling the thalamus and in some cases also the basal ganglia (caudate nucleus, 22 patients; and putamen, 4 patients). We applied visual analysis and signal quantification methods (Epileptogenicity Index [EI]) to their ictal recordings and compared electrophysiologic with clinical data. RESULTS: We found that in 86% of patients, thalamus was involved during seizures (visual analysis) and 20% showed high values of epileptogenicity (EI >0.3). Basal ganglia may also disclose high values of epileptogenicity (9% in caudate nucleus) but to a lesser degree than thalamus (p < 0.01). We observed different seizure onset patterns including low voltage high frequency activities. We found high values of thalamic epileptogenicity in different epilepsy localizations, including opercular and motor epilepsies. We found no difference between epilepsy etiologies (cryptogenic vs malformation of cortical development, p = 0.77). Thalamic epileptogenicity was correlated with the extension of epileptogenic networks (p = 0.02, ρ 0.32). We found a significant effect (p < 0.05) of thalamic epileptogenicity regarding the postsurgical outcome (higher thalamic EI corresponding to higher probability of surgical failure). CONCLUSIONS: Thalamic involvement during seizures is common in different seizure types. The degree of thalamic epileptogenicity is a possible marker of the epileptogenic network extension and of postsurgical prognosis.

The effect of medial pulvinar stimulation on temporal lobe seizures.

We investigated the effect of electrical stimulation of the medial pulvinar (PuM) in terms of its effect on temporal lobe seizures. Eight patients with drug-resistant temporal lobe epilepsy undergoing stereoelectroencephalographic exploration were included. All had at least one electrode exploring the PuM. High-frequency (50 Hz) stimulations of the PuM were well tolerated in the majority of them. During diagnostic stimulation to confirm the epileptogenic zone, 19 seizures were triggered by stimulating the hippocampus. During some of these seizures, ipsilateral pulvinar stimulation was applied (130 Hz, pulse width = 450 microseconds, duration = 3-7 seconds, 1-2 mA). Compared to non-PuM-stimulated seizures, five of eight patients experienced clinically less severe seizures, particularly in terms of degree of alteration of consciousness. On the electrical level, seizures were more rapidly clonic with a shorter tonic phase. This proof of concept study is the first to suggest that PuM stimulation could be a well-tolerated and effective means of therapeutic deep brain stimulation in drug-resistant epilepsies.

A prospective single-blind study of Gamma Knife thalamotomy for tremor.

OBJECTIVE: To evaluate the safety and efficacy of unilateral Gamma Knife thalamotomy (GKT) for treatment of severe tremor with a prospective blinded assessment. METHODS: Fifty patients (mean age: 74.5 years; 32 men) with severe refractory tremor (36 essential, 14 parkinsonian) were treated with unilateral GKT. Targeting of the ventral intermediate nucleus (Vim) was achieved with Leksell Gamma Knife with a single shot through a 4-mm collimator helmet. The prescription dose was 130 Gy. Neurologic and neuropsychological assessments including a single-blinded video assessment of the tremor severity performed by a movement disorders neurologist from another center were performed before and 12 months after treatment. MRI follow-up occurred at 3, 6, and 12 months. RESULTS: The upper limb tremor score improved by 54.2% on the blinded assessment (p < 0.0001). All tremor components (rest, postural, and intention) were improved. Activities of daily living were improved by 72.2%. Cognitive functions remained unchanged. Following GKT, the median delay of improvement was 5.3 months (range 1-12 months). The only side effect was a transient hemiparesis associated with excessive edema around the thalamotomy in one patient. CONCLUSION: This blinded prospective assessment demonstrates that unilateral GKT is a safe and efficient procedure for severe medically refractory tremor. Side effects were rare and transient in this study. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with severe refractory tremor, GKT is well tolerated and effective in reducing tremor impairment.

High-frequency cortical stimulation augments recovery of thalamocortical oscillations from hypoxia in rat brain slices.

OBJECTIVES: Cerebrovascular hypoxia results in severe impairment and electrical dysfunction of cortical and thalamic neuronal networks. Typically cellular electrical activity returns if reoxygenation is established within 5-8 min. Electrical stimulation has been shown to reduce cellular apoptosis following cerebral hypoxia in animal models and clinical case reports. In this study, we wanted to analyze the electrophysiological repercussions of electrical stimulation on recovery of spontaneous thalamocortical oscillations (TCOs) following hypoxia in a thalamocortical slice preparation. MATERIALS AND METHODS: A hypoxia model of rat thalamocortical brain slices was used in which spontaneous TCO and cortical oscillation (CO) activity could be tracked with extracellular and intracellular recording techniques. Spontaneous TCO and CO activity was recorded prior to, during, and after hypoxia was induced in 15 brain slices. Bipolar, high-frequency stimulation (100 µsec, 150 Hz, 3 V) of somatosensory cortex was applied immediately after reoxygenation of slices was started and its effect on return of TCO activity compared with non-stimulated slices. RESULTS: Depolarization and suppression of extracellular TCOs and COs were demonstrated following the induction of hypoxia. TCO activity was lost after an average of 2.7 ± 0.5 min of hypoxia, whereas COs activity remained for an additional 3.2 ± 0.3 min in the presence of hypoxia. After loss of both TCOs and COs, oxygenated perfusate was restarted and TCOs spontaneously recovered in 6.8 ± 0.42 min. When 10 sec of high-frequency cortical stimulation was applied at the beginning of oxygenated perfusion, TCOs were observed to recover within 2.8 ± 0.76 min. If oxygenated perfusate was not restarted within 2 min following loss of either TCOs or COs, no recovery was seen. CONCLUSIONS: High-frequency cortical stimulation accelerated the recovery of thalamocortical network activity following hypoxia and reperfusion. Insight into the underlying mechanisms of this effect may enhance therapeutic interventions related to hypoxia following ischemic stroke.