Is there a prediction network? Meta-analytic evidence for a cortical-subcortical network likely subserving prediction.

Predictive coding is an increasingly influential and ambitious concept in neuroscience viewing the brain as a 'hypothesis testing machine' that constantly strives to minimize prediction error, the gap between its predictions and the actual sensory input. Despite the invaluable contribution of this framework to the formulation of brain function, its neuroanatomical foundations have not been fully defined. To address this gap, we conducted activation likelihood estimation (ALE) meta-analysis of 39 neuroimaging studies of three functional domains (action perception, language and music) inherently involving prediction. The ALE analysis revealed a widely distributed brain network encompassing regions within the inferior and middle frontal gyri, anterior insula, premotor cortex, pre-supplementary motor area, temporoparietal junction, striatum, thalamus/subthalamus and the cerebellum. This network is proposed to subserve domain-general prediction and its relevance to motor control, attention, implicit learning and social cognition is discussed in light of the predictive coding scheme. Better understanding of the presented network may help advance treatments of neuropsychiatric conditions related to aberrant prediction processing and promote cognitive enhancement in healthy individuals.

Coaxial interleaved stimulation of the thalamus and subthalamus for treatment of Holmes tremor.

Holmes tremor is often treated with multiple deep brain stimulation (DBS) electrodes. The authors describe a novel technique to suppress the tremors by effectively utilizing a single electrode. A 16-year-old boy presented with severe right arm tremor following a midbrain injury. A DBS electrode was implanted into the ventral oralis nucleus of the thalamus (VO) and the subthalamic region. While individual stimulation of each target was ineffective, an interleaved dual stimulation of both targets has been effective for 6 years. Coaxial interleaved stimulation of the VO and the subthalamic region is useful for treating Holmes tremor. The video can be found here: https://youtu.be/tSwGh3vy68c .

Modulation of the cerebello-thalamo-cortical network in thalamic deep brain stimulation for tremor: a diffusion tensor imaging study.

BACKGROUND: Deep brain stimulation alleviates tremor of various origins. Several regions like the ventralis intermediate nucleus of thalamus, the caudal zona incerta, and the posterior subthalamic region are generally targeted. Previous work with fiber tractography has shown the involvement of the cerebello-thalamo-cortical network in tremor control. OBJECTIVE: To report the results of a prospective trial in a group of patients with tremor who underwent post hoc tractographic analysis after treatment with traditional thalamic deep brain stimulation. METHODS: A total of 11 patients (aged 64 ± 17 years, 6 male) were enrolled (essential tremor [6], Parkinson tremor [3], and myoclonic tremor in myoclonus dystonia [2]). Patients received 1 (3 patients), 2 (7 patients), or 3 (1 patient) quadripolar electrodes. A 32-direction diffusion tensor magnetic resonance imaging sequence was acquired preoperatively. Tractography was processed postoperatively for evaluation and the dentato-rubro-thalamic tract (DRT) was individually tracked. Electrode positions were determined with helical computed tomography. Electric fields (EFs) were simulated according to individual stimulation parameters in a standardized atlas brain space (ICBM-MNI 152). RESULTS: Tremor was reduced in all patients (69.4% mean) on the global (bilateral) tremor score. Effective contacts were located inside or in proximity to the DRT. In moderate tremor reduction (2 patients), the EFs were centered on its anterior border. In good and excellent tremor reduction (9 patients), EFs focused on its center. CONCLUSION: Deep brain stimulation of the cerebello-thalamo-cortical network reduces tremor. The DRT connects 3 traditional target regions for deep brain stimulation in tremor disease. Tractography techniques can be used to directly visualize the DRT and, therefore, optimize target definition in individual patients.

Individualized current-shaping reduces DBS-induced dysarthria in patients with essential tremor.

OBJECTIVE: To investigate in patients with essential tremor (ET) treated with thalamic/subthalamic deep brain stimulation (DBS) whether stimulation-induced dysarthria (SID) can be diminished by individualized current-shaping with interleaving stimulation (cs-ILS) while maintaining tremor suppression (TS). METHODS: Of 26 patients screened, 10 reported SID and were invited for testing. TS was assessed by the Tremor Rating Scale and kinematic analysis of postural and action tremor. SID was assessed by phonetic and logopedic means. Additionally, patients rated their dysarthria on a visual analog scale. RESULTS: In 6 of the 10 patients with ET, DBS-ON (relative to DBS-OFF) led to SID while tremor was successfully reduced. When comparing individualized cs-ILS with a non-current-shaped interleaving stimulation (ILS) in these patients, there was no difference in TS while 4 of the 6 patients showed subjective improvement of speech during cs-ILS. Phonetic analysis (ILS vs cs-ILS) revealed that during cs-ILS there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate, reflecting less dysarthria. Logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing ON with OFF but no difference between ILS and cs-ILS. CONCLUSION: This is a proof-of-principle evaluation of current-shaping in patients with ET treated with thalamic/subthalamic DBS and experiencing SID. Data suggest a benefit on SID from individual shaping of current spread while TS is preserved. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with ET treated with DBS with SID, individualized cs-ILS reduces dysarthria while maintaining tremor control.

Near-infrared stimulation on globus pallidus and subthalamus.

Near-infrared stimulation (NIS) is an emerging technique used to evoke action potentials in nervous systems. Its efficacy of evoking action potentials has been demonstrated in different nerve tissues. However, few studies have been performed using NIS to stimulate the deep brain structures, such as globus pallidus (GP) and subthalamic nucleus (STN). Male Sprague-Dawley rats were randomly divided into GP stimulation group (n=11) and STN stimulation group (n=6). After introducing optrodes stereotaxically into the GP or STN, we stimulated neural tissue for 2 min with continuous near-infrared light of 808 nm while varying the radiant exposure from 40 to 10 mW. The effects were investigated with extracellular recordings and the temperature rises at the stimulation site were also measured. NIS was found to elicit excitatory responses in eight out of 11 cases (73%) and inhibitory responses in three cases in the GP stimulation group, whereas it predominantly evoked inhibitory responses in seven out of eight cases (87.5%) and an excitatory response in one case in STN stimulation group. Only radiation above 20 mW, accompanying temperature increases of more than 2°C, elicited a statistically significant neural response (p<0.05). The responsiveness to NIS was linearly dependent on the power of radiation exposure.

Motor cortex stimulation activates the incertothalamic pathway in an animal model of spinal cord injury.

UNLABELLED: We have shown previously that electrical stimulation of the motor cortex reduces spontaneous painlike behaviors in animals with spinal cord injury (SCI). Because SCI pain behaviors are associated with abnormal inhibition in the inhibitory nucleus zona incerta (ZI) and because inactivation of the ZI blocks motor cortex stimulation (MCS) effects, we hypothesized that the antinociceptive effects of MCS are due to enhanced inhibitory inputs from ZI to the posterior thalamus (Po)-an area heavily implicated in nociceptive processing. To test this hypothesis, we used a rodent model of SCI pain and performed in vivo extracellular electrophysiological recordings in single well-isolated neurons in anesthetized rats. We recorded spontaneous activity in ZI and Po from 48 rats before, during, and after MCS (50 µA, 50 Hz; 300-ms pulses). We found that MCS enhanced spontaneous activity in 35% of ZI neurons and suppressed spontaneous activity in 58% of Po neurons. The majority of MCS-enhanced ZI neurons (81%) were located in the ventrorateral subdivision of ZI-the area containing Po-projecting ZI neurons. In addition, we found that inactivation of ZI using muscimol (GABAA receptor agonist) blocked the effects of MCS in 73% of Po neurons. Although we cannot eliminate the possibility that muscimol spread to areas adjacent to ZI, these findings support our hypothesis and suggest that MCS produces antinociception by activating the incertothalamic pathway. PERSPECTIVE: This article describes a novel brain circuit that can be manipulated, in rats, to produce antinociception. These results have the potential to significantly impact the standard of care currently in place for the treatment of patients with intractable pain.

Thalamic and subthalamic deep brain stimulation for essential tremor: where is the optimal target?

BACKGROUND: The ventrolateral thalamus (ventral intermediate nucleus [Vim]) is the traditional target for neurosurgical treatment of essential tremor. The target, however, has varied substantially among different neurosurgeons. OBJECTIVE: To evaluate the effect of deep brain stimulation in the thalamus and posterior subthalamic area (PSA) in relation to electrode location. METHODS: Thirty-six (17 Vim/19 PSA) patients with 44 deep brain stimulation electrodes were included in this retrospective study. The effect of stimulation was evaluated with standardized settings for each contact using items from the Essential Tremor Rating Scale. RESULTS: When each contact was evaluated in terms of the treated hand with standardized stimulation, the electrode contact providing the best effect in the individual patient was located in the zona incerta or radiation prelemniscalis in 54% and the Vim in 12%. Forty contacts provided a tremor reduction of > 90%. Of these, 43% were located in the PSA and 18% in the Vim according to the Schaltenbrand atlas. Of these 40 contacts, 37 were found in the PSA group. CONCLUSION: More contacts yielding an optimal effect were found in the PSA group than in the Vim. Many patients operated on in the Vim got the best effect from a contact located in the PSA. This might suggest that the PSA is a more efficient target than the Vim.

Hidden semi-Markov models in the computerized decoding of microelectrode recording data for deep brain stimulator placement.

OBJECTIVE: To describe an approach to the analysis of deep brain stimulation (DBS) of the subthalamic nucleus (STN) using a hidden semi-Markov model (HsMM) and early results of the analysis of microelectrode recordings for STN DBS. METHODS: The author simulated the anatomy and electrophysiology of STN DBS and built a seven-state model to compare Hidden Markov model (HMM) and HsMM approaches. RESULTS: Accuracy of these competing models was similar for correctly identifying brain nuclei; however, HsMMs showed superior specificity in detecting microelectrode passes traversing the STN. CONCLUSIONS: Further clinical work must be done; however, based on these data, HsMMs may be best suited to computer-assisted anatomic delineation for DBS.

Influence of age, gender and severity of tremor on outcome after thalamic and subthalamic DBS for essential tremor.

Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). The nucleus ventralis intermedius thalami (Vim) is the target of choice, but promising results have been presented regarding DBS in the posterior subthalamic area (PSA). The aim of this study was to evaluate the possible influence of gender, age and severity of disease on the outcome of these procedures. Sixty eight patients (34 Vim, 34 PSA) with ET were included in this non-randomised study. Evaluation using the Essential Tremor Rating Scale (ETRS) was performed before, and one year after surgery concerning PSA DBS, and at a mean of 28 ± 24 months concerning Vim DBS. Items 5/6 and 11-14 (hand tremor and hand function) were selected for analysis of tremor outcome. The efficacy of DBS on essential tremor was not related to age or gender. Nor was it associated with the severity of tremor when the percentual reduction of tremor on stimulation was taken into account. However, patients with a more severe tremor at baseline had a higher degree of residual tremor on stimulation. Tremor in the treated hand and hand function were improved with 70% in the Vim group and 89% in the PSA group.

Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response.

Placebo administration to Parkinson patients is known to induce dopamine release in the striatum and to affect the activity of subthalamic nucleus (STN) neurons. By using intraoperative single-neuron recording techniques in awake patients, here we extend our previous study on STN recording, and characterize part of the neuronal circuit which is affected by placebos. In those patients who showed a clinical placebo response, there was a decrease in firing rate in STN neurons that was associated with a decrease in the substantia nigra pars reticulata (SNr) and an increase in the ventral anterior (VA) and anterior ventral lateral (VLa) thalamus. These data show that placebo decreases STN and SNr activity whereas it increases VA/VLa activity. By contrast, placebo non-responders showed either a lack of changes in this circuit or partial changes in the STN only. Thus, changes in activity in the whole basal ganglia-VA/VLa circuit appear to be important in order to observe a clinical placebo improvement, although the involvement of other circuits, such as the direct pathway bypassing the STN, cannot be ruled out. The circuit we describe in the present study is likely to be a part of a more complex circuitry, including the striatum and the internal globus pallidus (GPi), that is modified by placebo administration. These findings indicate that a placebo treatment, which is basically characterized by verbal suggestions of benefit, can reverse the malfunction of a complex neuronal circuit, although these placebo-associated neuronal changes are short-lasting and occur only in some patients but not in others.

Subthalamic stimulation improves orienting gaze movements in Parkinson's disease.

OBJECTIVE: To determine the effect of subthalamic stimulation on visually triggered eye and head movements in patients with Parkinson's disease (PD). METHODS: We compared the gain and latency of visually triggered eye and head movements in 12 patients bilaterally implanted into the subthalamic nucleus (STN) for severe PD and six age-matched control subjects. Visually triggered movements of eye (head restrained), and of eye and head (head unrestrained) were recorded in the absence of dopaminergic medication. Bilateral stimulation was turned OFF and then turned ON with voltage and contact used in chronic setting. The latency was determined from the beginning of initial horizontal eye movements relative to the target onset, and the gain was defined as the ratio of the amplitude of the initial movement to the amplitude of the target movement. RESULTS: Without stimulation, the initiation of the head movement was significantly delayed in patients and the gain of head movement was reduced. Our patients also presented significantly prolonged latencies and hypometry of visually triggered saccades in the head-fixed condition and of gaze in head-free condition. Bilateral STN stimulation with therapeutic parameters improved performance of orienting gaze, eye and head movements towards the controls' level CONCLUSIONS: These results demonstrate that visually triggered saccades and orienting eye-head movements are impaired in the advanced stage of PD. In addition, subthalamic stimulation enhances amplitude and shortens latency of these movements. SIGNIFICANCE: These results are likely explained by alteration of the information processed by the superior colliculus (SC), a pivotal visuomotor structure involved in both voluntary and reflexive saccades. Improvement of movements with stimulation of the STN may be related to its positive input either on the STN-Substantia Nigra-SC pathway or on the parietal cortex-SC pathway.

Motor cortex gates vibrissal responses in a thalamocortical projection pathway.

Higher-order thalamic nuclei receive input from both the cerebral cortex and prethalamic sensory pathways. However, at rest these nuclei appear silent due to inhibitory input from extrathalamic regions, and it has therefore remained unclear how sensory gating of these nuclei takes place. In the rodent, the ventral division of the zona incerta (ZIv) serves as a relay station within the paralemniscal thalamocortical projection pathway for whisker-driven motor activity. Most, perhaps all, ZIv neurons are GABAergic, and recent studies have shown that these cells participate in a feedforward inhibitory circuit that blocks sensory transmission in the thalamus. The present study provides evidence that the stimulation of the vibrissa motor cortex suppresses vibrissal responses in ZIv via an intra-incertal GABAergic circuit. These results provide support for the proposal that sensory transmission operates via a top-down disinhibitory mechanism that is contingent on motor activity.

The pallidofugal motor fiber system in primates.

The organization of the pallidofugal fiber system originating from the internal segment of the globus pallidus (GPi) in cynomolgus monkeys (Macaca fascicularis) was studied by means of a single-axon tracing method. The primate GPi is composed of a majority of neurons endowed with a highly collateralized axon that projects to the premotor neurons located in the ventral tier thalamic nuclei, the center-médian/parafascicular thalamic complex and the brainstem pedunculopontine nucleus. These axons often follow a long and tortuous course within the GPi and then emerge either through the ansa lenticularis (AL) or the lenticular fasciculus (LF), irrespective of the location of their parent cell body in the GPi. Other pallidofugal axons exit through the medial pole of the GPi, at various distances between the AL ventrally and the LF dorsally. Virtually all pallidofugal axons course through Forel's field H, on their way to the thalamus and brainstem. They emit numerous short collaterals and boutons en passant in this sector of the subthalamic region, which stands out as a major target of GPi axons. Our results indicate that AL and LF do not form separate anatomical entities, each carrying axons originating from distinct functional pallidal territories, as commonly believed. Instead, these two fascicles form the ventral and dorsal borders of a morphological continuum that harbors a multitude of pallidofugal axons arising from all sectors of the GPi. This type of information should be taken into account when interpreting data from deep brain stimulation applied to pallidal and subthalamic regions in Parkinson's disease.

Subthalamic deep brain stimulation improves time perception in Parkinson's disease.

Alterations in temporal estimation have been observed in Parkinson's disease (PD) and have been associated with dopaminergic dysfunction. To investigate whether deep brain stimulation might reverse these abnormalities in PD, patients treated with electrode implantation for subthalamic deep brain stimulation were required to reproduce time intervals in different experimental conditions (off deep brain stimulation/off therapy, on deep brain stimulation/off therapy, on therapy/off deep brain stimulation). Patients treated with deep brain stimulation in off deep brain stimulation/off therapy displayed the anomalous pattern of responses typically observed in PD. When subthalamic deep brain stimulation was turned on these abnormalities were significantly attenuated. Our findings reveal that subthalamic deep brain stimulation improves time perception in PD patients, supporting the critical role of basal ganglia in this cognitive function, probably mediated by facilitated thalamo-cortical projections to the prefrontal cortex.

Electrical stimulation of the brain in Wilson-Konovalov hepatocerebral dystrophy (a neuromorphological and neurophysiological analysis).

Stereotaxic surgery was performed in 27 patients. Complete elimination of or significant reductions in hyperkinesia were obtained in 17 cases; five patients died. There was no correlation between the severity of clinical manifestations of hepatocellular dystrophy and the relatively normal quantitative measures of cortical and subcortical biopotentials, which were produced on a background of microstructural changes affecting neurons in these regions. It is suggested that qualitative significance of these biopotentials is that they carry an excess pathological spike activity resulting in hyperkinesia. This is supported by the fact that hyperkinesia was suppressed after surgical destruction of the ventrolateral nucleus of the thalamus and subthalamic structures.

Intrathalamic non-propagating generators of high-frequency (1000 Hz) somatosensory evoked potential (SEP) bursts recorded subcortically in man.

OBJECTIVES: Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. METHODS: During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites +20 and +10 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. RESULTS: Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. CONCLUSIONS: Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation.

Hypothalamic and zona incerta neurons in sheep, initially only responding to the sight of food, also respond to the sight of water after intracerebroventricular injection of hypertonic saline or angiotensin II.

Extracellular single-unit recordings were made from neurons in the lateral hypothalamus (LH) or zona incerta (ZI) of conscious sheep. A small population of neurons (12/83) were found which responded with increased firing rate when the animal looked at food but did not respond when the sheep looked at water. The effects of rapidly inducing intense thirst by the intracerebroventricular (i.c.v.) injection of hypertonic (0.85 M) saline or 200 ng of angiotensin II, or a mixture of the two dipsogenic stimuli, on the response of neurons initially responding only to the sight of food were investigated. Following i.c.v. injection of the dipsogenic stimuli the neurons began to respond strongly to the sight of water. The results demonstrated that changing the animal's motivational state alters the response of some neurons in the LH and ZI and suggests that the neuronal response is influenced by the animal's dominant need at the time of testing.