Pallidal Stimulation Modulates Pedunculopontine Nuclei in Parkinson's Disease.

BACKGROUND: In advanced Parkinson’s disease, the pedunculopontine nucleus region is thought to be abnormally inhibited by gamma-aminobutyric acid (GABA) ergic inputs from the over-active globus pallidus internus. Recent attempts to boost pedunculopontine nucleus function through deep brain stimulation are promising, but suffer from the incomplete understanding of the physiology of the pedunculopontine nucleus region. METHODS: Local field potentials of the pedunculopontine nucleus region and the globus pallidus internus were recorded and quantitatively analyzed in a patient with Parkinson’s disease. In particular, we compared the local field potentials from the pedunculopontine nucleus region at rest and during deep brain stimulation of the globus pallidus internus. RESULTS: At rest, the spectrum of local field potentials in the globus pallidus internus was mainly characterized by delta-theta and beta frequency activity whereas the spectrum of the pedunculopontine nucleus region was dominated by activity only in the delta and theta band. High-frequency deep brain stimulation of the globus pallidus internus led to increased theta activity in the pedunculopontine nucleus region and enabled information exchange between the left and right pedunculopontine nuclei. Therefore, Conclusions: When applying deep brain stimulation in the globus pallidus internus, its modulatory effect on pedunculopontine nucleus physiology should be taken into account.

Interhemispheric connectivity in amyotrophic lateral sclerosis: A near-infrared spectroscopy and diffusion tensor imaging study.

PURPOSE: Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS. MATERIAL AND METHODS: Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains. RESULTS: ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs (p = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = - 0.85, p = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI (p < 0.05). CONCLUSIONS: The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs.

Near-infrared spectroscopy and transcranial sonography to evaluate cerebral autoregulation in middle cerebral artery steno-occlusive disease.

The measurement of autoregulatory delay by near-infrared spectroscopy (NIRS) has been proposed as an alternative technique to assess cerebral autoregulation, which is routinely assessed via transcranial Doppler sonography (TCD) in most centers. Comparitive studies of NIRS and TCD, however, are largely missing. We investigated whether cerebrovascular reserve (CVR), as assessed via TCD, correlates with the delay of the autoregulatory response to changes in arterial blood pressure (ABP) as assessed by NIRS, i.e., if impaired upstream vasomotor reactivity is reflected by downstream cortical autoregulation. Twenty patients with unilateral high-grade steno-occlusion of the middle cerebral artery (MCA) underwent bilateral multichannel NIRS of the cortical MCA distributions over a period of 6 min while breathing at a constant rate of 6 cycles/min to induce stable oscillations in ABP. The phase shift φ between ABP and cortical blood oxygenation was calculated as a measure of autoregulatory latency. In a subgroup of 13 patients, CO2 reactivity of the MCAs was determined by TCD to assess CVR in terms of normalized autoregulatory response (NAR). Mean phase shift between ABP and blood oxygenation was significantly increased over the hemisphere ipsilateral to the steno-occlusion (n = 20, p = 0.042). The interhemispheric difference Δφ in phase shift was significantly larger in patients with markedly diminished or exhausted CVR (NAR < 10) than in patients with normal NAR values (NAR ≥ 10) (p = 0.007). Within the MCA core distribution territory, a strong correlation existed between Δφ and CO2 reactivity of the affected MCA (n = 13, r = -0.78, p = 0.011). NIRS may provide an alternative or supplementary approach to evaluate cerebral autoregulation in risk assessment of ischemic events in steno-occlusive disease of cerebral arteries, especially in patients with insufficient bone windows for TCD.

Clinical, neuropsychological, and pre-stimulus dorsomedial thalamic nucleus electrophysiological data in deep brain stimulation patients.

The data presented here comprise clinical, neuropsychological, and intrathalamic electrophysiological data from 7 patients with pharmacoresistant focal epilepsy and are related to the article "Pre-stimulus thalamic theta power predicts human memory formation" C.M. Sweeney-Reed, T. Zaehle, J. Voges, F.C. Schmitt, L. Buentjen, K. Kopitzki, et al. (2016) [1]. The patients participated in a memory paradigm after receiving electrodes implanted in the DMTN due to the surgical approach taken in electrode insertion for deep brain stimulation of the anterior thalamic nucleus. Epilepsy duration and pre-operative neuropsychological tests provide an indication of the profile of patients receiving intrathalamic electrode implantation and the memory capabilities in such a patient group. The electrophysiological data were recorded from the right DMTN preceding stimulus presentation during intentional memory encoding. The patients viewed a series of photographic scenes, which they judged as indoors or outdoors. The 900 ms epochs prior to stimulus presentation were labeled as preceding successful or unsuccessful subsequent memory formation according to a subsequent memory test for the items. The difference between theta power preceding successful versus unsuccessful subsequent memory formation is shown against time for each patient individually.

Pre-stimulus thalamic theta power predicts human memory formation.

Pre-stimulus theta (4-8Hz) power in the hippocampus and neocortex predicts whether a memory for a subsequent event will be formed. Anatomical studies reveal thalamus-hippocampal connectivity, and lesion, neuroimaging, and electrophysiological studies show that memory processing involves the dorsomedial (DMTN) and anterior thalamic nuclei (ATN). The small size and deep location of these nuclei have limited real-time study of their activity, however, and it is unknown whether pre-stimulus theta power predictive of successful memory formation is also found in these subcortical structures. We recorded human electrophysiological data from the DMTN and ATN of 7 patients receiving deep brain stimulation for refractory epilepsy. We found that greater pre-stimulus theta power in the right DMTN was associated with successful memory encoding, predicting both behavioral outcome and post-stimulus correlates of successful memory formation. In particular, significant correlations were observed between right DMTN theta power and both frontal theta and right ATN gamma (32-50Hz) phase alignment, and frontal-ATN theta-gamma cross-frequency coupling. We draw the following primary conclusions. Our results provide direct electrophysiological evidence in humans of a role for the DMTN as well as the ATN in memory formation. Furthermore, prediction of subsequent memory performance by pre-stimulus thalamic oscillations provides evidence that post-stimulus differences in thalamic activity that index successful and unsuccessful encoding reflect brain processes specifically underpinning memory formation. Finally, the findings broaden the understanding of brain states that facilitate memory encoding to include subcortical as well as cortical structures.

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods.

Thalamic theta phase alignment predicts human memory formation and anterior thalamic cross-frequency coupling.

Previously we reported electrophysiological evidence for a role for the anterior thalamic nucleus (ATN) in human memory formation (Sweeney-Reed et al., 2014). Theta-gamma cross-frequency coupling (CFC) predicted successful memory formation, with the involvement of gamma oscillations suggesting memory-relevant local processing in the ATN. The importance of the theta frequency range in memory processing is well-established, and phase alignment of oscillations is considered to be necessary for synaptic plasticity. We hypothesized that theta phase alignment in the ATN would be necessary for memory encoding. Further analysis of the electrophysiological data reveal that phase alignment in the theta rhythm was greater during successful compared with unsuccessful encoding, and that this alignment was correlated with the CFC. These findings support an active processing role for the ATN during memory formation.

Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation.

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.

Lesion focused stereotactic thermo-coagulation of focal cortical dysplasia IIB: a new approach to epilepsy surgery?

PURPOSE: Over the last few decades, preferred epilepsy surgical approaches have developed from standard lobectomies to individually tailored resections. Yet, it remains uncertain how small surgical interventions can be without compromising the success of the surgery. Particularly in patients with epileptogenic lesions identified by magnetic resonance imaging (MRI), it is unresolved whether resection or destruction of the lesion suffices to eliminate the epileptogenic zone. We present a minimally invasive surgical approach that may provide insight into this issue. METHODS: Two patients with pharmacoresistant epilepsy due to focal cortical dysplasia type IIB demonstrated by 3 Tesla MRI were treated with lesion-focused stereotactic radio-frequency thermo-coagulation. In both patients, pathognomonic epileptic discharges were recorded from the lesion via a stimulation device prior to coagulation. In one patient, the suspected proximity of the lesion to the pyramidal tract was verified by eliciting motor evoked potentials from the depths of the lesion. RESULTS: Following complete and near complete lesion destruction, seizures (several per day or per week, respectively) ceased in patients A and B, with no seizures for 12 months and 5 months, respectively, at the time of this publication. Neither patient acquired persistent postoperative neurological deficits. CONCLUSION: The fact that seizure activity stopped after destruction of small bottom-of-sulcus dysplasias implies that in these cases, the epileptogenic zone and the epileptogenic lesion may overlap. If future studies can replicate this finding, focused lesion destruction could be a further development of individually tailored epilepsy surgery. The technique described here is especially suited for high-precision surgery close to eloquent brain structures.

Direct targeting of the thalamic anteroventral nucleus for deep brain stimulation by T1-weighted magnetic resonance imaging at 3 T.

BACKGROUND: The thalamic anteroventral nucleus (AV) is a promising target structure for deep brain stimulation (DBS) in patients suffering from refractory epilepsy. Direct visualization of the AV would improve spatial accuracy in functional stereotactic neurosurgery for treatment of this disease. METHODS: On 3-tesla magnetic resonance imaging (MRI), acquisition parameters were adjusted for optimal demarcation of the AV in 1 healthy subject. Reliability of AV visualization was then evaluated in 5 healthy individuals and 3 patients with refractory epilepsy. RESULTS: In all individuals, an adjusted T1-weighted sequence allowed for demarcation of the AV. It was clearly distinguishable from hyperintense myelin-rich lamellae surrounding it ventrally and laterally and appeared hypo-intense compared to the adjacent thalamic nuclei. Image resolution and contrast facilitated direct stereotactic targeting of the AV prior to DBS surgery in all 3 patients. CONCLUSIONS: Direct targeting of the AV can be achieved, which has immediate implications for the accuracy of MRI-guided DBS in patients with refractory epilepsy.

Phase-amplitude cross-frequency coupling in the human nucleus accumbens tracks action monitoring during cognitive control.

The Nucleus Accumbens (NAcc) is an important structure for the transfer of information between cortical and subcortical structures, especially the prefrontal cortex and the hippocampus. However, the mechanism that allows the NAcc to achieve this integration is not well understood. Phase-amplitude cross-frequency coupling (PAC) of oscillations in different frequency bands has been proposed as an effective mechanism to form functional networks to optimize transfer and integration of information. Here we assess PAC between theta and high gamma oscillations as a potential mechanism that facilitates motor adaptation. To address this issue we recorded intracranial field potentials directly from the bilateral human NAcc in three patients while they performed a motor learning task that varied in the level of cognitive control needed to perform the task. As in rodents, PAC was observable in the human NAcc, transiently occurring contralateral to a movement following the motor response. Importantly, PAC correlated with the level of cognitive control needed to monitor the action performed. This functional relation indicates that the NAcc is engaged in action monitoring and supports the evaluation of motor programs during adaptive behavior by means of PAC.

Assessment of cortical hemodynamics by multichannel near-infrared spectroscopy in steno-occlusive disease of the middle cerebral artery.

BACKGROUND AND PURPOSE: In a pilot study we evaluated near-infrared spectroscopy as to its potential benefit in monitoring patients with steno-occlusive disease of a major cerebral artery for alterations in cortical hemodynamics. METHODS: Cortical maps of time-to-peak (TTP) in 10 patients unilaterally affected by severe stenosis or occlusion of the middle cerebral artery were acquired by multichannel near-infrared spectroscopy after bolus application of indocyanine green. Hemodynamic manifestations were assessed by comparison between affected and unaffected hemisphere and evaluated for common constituents by principal component analysis. In one patient, TTP values were compared with those obtained by dynamic susceptibility contrast imaging. RESULTS: TTP was increased on the affected hemisphere in 9 patients. Mean difference in TTP between hemispheres was 0.44 second (P<0.05) as compared with a mean lateral difference of 0.12 second found in a control group of 10 individuals. In group analysis a significant rise in TTP was found in the distribution of the affected middle cerebral artery, whereas principal component analysis suggests augmentation of hemodynamic effects toward the border zones as a dominant pattern. A linear correlation of 0.61 between TTP values determined by dynamic susceptibility contrast MRI and near-infrared spectroscopy was found to be statistically significant (P<0.001). CONCLUSIONS: Multichannel near-infrared spectroscopy might facilitate detection of disease-related hemodynamic changes as yet only accessible by tomographic imaging modalities. Being indicative for hypoperfusion and collateral flow increased values of TTP, as found to a varying extent in the present patient group, might be of clinical relevance.

Capillary physiology of human medulloblastoma: impact on chemotherapy.

BACKGROUND: Advances in the treatment of medulloblastoma have largely been attributed to the introduction of chemotherapy, although Phase III trials have shown advantages for chemotherapy only in subgroups. Because the efficacy of chemotherapy depends on tumor vascularization, the vascular physiology of human medulloblastomas was evaluated. METHODS: Seven patients with histologically proven medulloblastomas underwent measurements of capillary permeability and vascular plasma volume using contrast-enhanced dynamic computer tomography. Regional blood flow was measured in 5 patients using xenon computed tomography (CT). RESULTS: The capillary permeability-surface product for water-soluble compounds ranged from 1.7 +/- 5.5 to 17.6 +/- 12.3 muL/g/min with a mean of 10.5 +/- 6.3 microL/g/min. The vascular plasma volume ranged from 0.02 +/- 0.021 to 0.045 +/- 0.049 mL/g with a mean of 0.03 +/- 0.01 mL/g. The efflux rate ranged from 0.012 +/- 0.007 to 0.065 +/- 0.064 1/min with a mean of 0.039 +/- 0.020 1/min. Regional tumoral blood flow showed a mean of 19.86 +/- 6.8 mL/100g/min as compared with normal cerebellum with 45.4 +/- 12.03 mL/100g/min (P < .005). CONCLUSIONS: The current study demonstrated a low capillary permeability and blood flow in medulloblastomas that could explain the limited response rates of partially resected tumors even after aggressive high-dose chemotherapy, as recently reported.

Capillary physiology and drug delivery in central nervous system lymphomas.

To evaluate whether the chemosensitivity of primary central nervous system lymphomas to water-soluble drugs could result from improved drug delivery, we quantitatively assessed pharmacokinetic factors in seven patients. The capillary permeability surface product was found to be significantly increased in central nervous system lymphomas compared with glioblastoma multiforme, medulloblastomas, and metastases. Tumoral blood flow was significantly greater than in normal white matter. Our results suggest favorable pharmacokinetics to water- and lipid-soluble drugs in primary central nervous system lymphomas.