Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes.

Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson's disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson's disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity-bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

Can the RAVLT predict deterioration from MCI to dementia? Data from long term follow up.

OBJECTIVE: To assess whether the Rey Auditory Verbal Learning Test (RAVLT) could differentiate deterioration from Mild Cognitive Impairment (MCI) to dementia. METHODS: Twenty-six participants who were diagnosed with MCI performed the RAVLT and the Mini Mental State Examination (MMSE) at baseline and after nearly a decade (M = 8.8 years, SD = 3.16), in order to evaluate whether they progressed to dementia. RESULTS: Twelve participants [5 males, 7 females; age M = 63.7 (7.7)] kept their diagnoses of MCI; 14 participants [11 males, 3 females; age M = 75.0 (6.5)] converted to dementia. Both groups had similar MMSE scores at baseline [26.6 (0.6); and 26.6 (0.7) respectively]. Significant differences between dementia and MCI groups were found on most measures of the RAVLT at baseline: Immediate memory [p = .04], delayed recall [p = .003], total learning [p = .01], learning rate [p = .002], retrieval efficiency [p = .004], and false alarms [p = .004]. Thus, the RAVLT results were significantly worse at baseline in those who later converted. The results remain the same when controlling for age. CONCLUSION: The results extend previous findings with follow-up of nearly a decade demonstrating that most of the RAVLT measures are sensitive to differentiate conversion from MCI to dementia.

Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.

OBJECTIVE: Experiential phenomena (EP), such as illusions and complex hallucinations, are vivid experiences created in one's mind. They can occur spontaneously as epileptic auras or can be elicited by electrical brain stimulation (EBS) in patients undergoing presurgical evaluation for drug-resistant epilepsy. Previous work suggests that EP arise from activation of different nodes within interconnected neural networks mainly in the temporal lobes. Yet, the anatomical extent of these neural networks has not been described and the question of lateralization of EP has not been fully addressed. To this end, an extended number of brain regions in which electrical stimulation elicited EP were studied to test whether there is a lateralization propensity to EP phenomena. METHODS: A total of 19 drug-resistant focal epilepsy patients who underwent EBS as part of invasive presurgical evaluation and who experienced EP during the stimulation were included. Spatial dispersion of visual and auditory illusions and complex hallucinations in each hemisphere was determined by calculation of Euclidean distances between electrodes and their centroid in common space, based on (x, y, z) Cartesian coordinates of electrode locations. RESULTS: In total, 5857 stimulation epochs were analyzed; 917 stimulations elicited responses, out of which 130 elicited EP. Complex visual hallucinations were found to be widely dispersed in the right hemisphere, while they were tightly clustered in the occipital lobe of the left hemisphere. Visual illusions were elicited mostly in the occipital lobes bilaterally. Auditory illusions and hallucinations were evoked symmetrically in the temporal lobes. CONCLUSIONS: These findings suggest that complex visual hallucinations arise from wider spread in the right compared to the left hemisphere, possibly mirroring the asymmetry in the white matter organization of the two hemispheres. These results offer some insights into lateralized differences in functional organization and connectivity that may be important for functional mapping and planning of surgical resections in patients with epilepsy.

The Impact of Colloid Cyst Treatment on Neurocognition.

BACKGROUND: Colloid cysts (CC) have been associated with neurocognitive function (NCF) decline, both preoperatively and after resection. Factors such as local pressure on the fornix and hydrocephalus are thought to contribute to preoperative NCF decline. The potential cause of postoperative decline is thought to be forniceal injury during surgery. In the current series, we describe NCF outcomes amongst patients with CC, both nonoperated and operated. METHODS: A total of 36 patients (23 operated, 13 nonoperated) were included in this retrospective study. All patients underwent at least 1 NCF evaluation battery. Of the 13 nonoperated cases, 5 had follow-up tests too. Of the 23 operated, 14 had both pre- and postoperative tests, and 8 had early and late postoperative tests. RESULTS: There was no significant difference in baseline NCF between nonoperated and operated cases (as evaluated preoperatively). Nonoperated patients had a stable NCF test over time. Patients who were operated showed a significant improvement after surgery in several NCF variables. There was no significant change in NCF between early and late postoperative evaluation. None of the operated patients had a postoperative NCF decline. CONCLUSIONS: Patients with CC should undergo routine NCF testing with a standardized protocol, whether they are operated or followed. Surgery has a positive impact on NCF; however, it remains to be determined if the improvement is solely secondary to treatment of hydrocephalus, or to a reduction of local pressure on the fornices. It remains to be determined whether the surgical technique, that is, endoscopic, interhemispheric, or transcortical, has an impact on NCF outcome.

Near-total absence of REM sleep co-occurring with normal cognition: an update of the 1984 paper.

BACKGROUND: REM sleep (REMS) is considered vital for supporting well-being and normal cognition. However, it remains unclear if and how decreases in REMS impair cognitive abilities. Rare case studies of patients with REMS abolishment due to pontine lesions remain sporadic, and formal evaluation of cognitive status is lacking. In 1984, Lavie and colleagues described the case of Y.C. - a man with a pontine lesion and near-total absence of REMS who led a normal life. Here, we set out to re-evaluate this individual's REMS status 30 years after the original report, and formally assess his cognitive abilities. METHODS: Four whole-night polysomnographic sleep recordings were conducted to evaluate sleep architecture. Sleep scoring was performed according to the American Academy of Sleep Medicine (AASM) guidelines. Cranial Computed Tomography (CT) imaging was performed, as well as formal neuropsychological testing to evaluate cognitive functions. RESULTS: Y.C. averaged 4.5% of sleep time in REMS, corresponding to the 0.055 percentile of normal values for his age. Furthermore, residual REMS episodes were short and only occurred towards the end of the night. CT imaging revealed damage and metallic fragments in pons, cerebellum, and thalamus. Neuropsychological evaluation demonstrated average to high-average cognitive skills, normal memory, and motor difficulties including speech and left hand dyspraxia. CONCLUSIONS: To our knowledge, this is the only case where REMS loss resulting from pontine lesion was re-evaluated after many years. We find a near-total absence of REMS with no signs of significant compensation throughout adult life, along with normal cognitive status. The results provide a unique perspective on the ongoing debate regarding the functional role of REMS in supporting cognition.

Probabilistic machine learning for the evaluation of presurgical language dominance.

OBJECTIVE Providing a reliable assessment of language lateralization is an important task to be performed prior to neurosurgery in patients with epilepsy. Over the last decade, functional MRI (fMRI) has emerged as a useful noninvasive tool for language lateralization, supplementing or replacing traditional invasive methods. In standard practice, fMRI-based language lateralization is assessed qualitatively by visual inspection of fMRI maps at a specific chosen activation threshold. The purpose of this study was to develop and evaluate a new computational technique for providing the probability of each patient to be left, right, or bilateral dominant in language processing. METHODS In 76 patients with epilepsy, a language lateralization index was calculated using the verb-generation fMRI task over a wide range of activation thresholds (from a permissive threshold, analyzing all brain regions, to a harsh threshold, analyzing only the strongest activations). The data were classified using a probabilistic logistic regression method. RESULTS Concordant results between fMRI and Wada lateralization were observed in 89% of patients. Bilateral and right-dominant groups showed similar fMRI lateralization patterns differentiating them from the left-dominant group but still allowing classification in 82% of patients. CONCLUSIONS These findings present the utility of a semi-supervised probabilistic learning approach for presurgical language-dominance mapping, which may be extended to other cognitive domains such as memory and attention.

Distinct iEEG activity patterns in temporal-limbic and prefrontal sites induced by emotional intentionality.

Our emotions tend to be directed towards someone or something. Such emotional intentionality calls for the integration between two streams of information; abstract hedonic value and its associated concrete content. In a previous functional magnetic resonance imaging (fMRI) study we found that the combination of these two streams, as modeled by short emotional music excerpts and neutral film clips, was associated with synergistic activation in both temporal-limbic (TL) and ventral-lateral PFC (vLPFC) regions. This additive effect implies the integration of domain-specific 'affective' and 'cognitive' processes. Yet, the low temporal resolution of the fMRI limits the characterization of such cross-domain integration. To this end, we complemented the fMRI data with intracranial electroencephalogram (iEEG) recordings from twelve patients with intractable epilepsy. As expected, the additive fMRI activation in the amygdala and vLPFC was associated with distinct spatio-temporal iEEG patterns among electrodes situated within the vicinity of the fMRI activation foci. On the one hand, TL channels exhibited a transient (0-500 msec) increase in gamma power (61-69 Hz), possibly reflecting initial relevance detection or hedonic value tagging. On the other hand, vLPFC channels showed sustained (1-12 sec) suppression of low frequency power (2.3-24 Hz), possibly mediating changes in gating, enabling an on-going readiness for content-based processing of emotionally tagged signals. Moreover, an additive effect in delta-gamma phase-amplitude coupling (PAC) was found among the TL channels, possibly reflecting the integration between distinct domain specific processes. Together, this study provides a multi-faceted neurophysiological signature for computations that possibly underlie emotional intentionality in humans.

Emergence of sensory patterns during sleep highlights differential dynamics of REM and non-REM sleep stages.

Despite the profound reduction in conscious awareness associated with sleep, sensory cortex remains highly active during the different sleep stages, exhibiting complex interactions between different cortical sites. The potential functional significance of such spatial patterns and how they change between different sleep stages is presently unknown. In this electrocorticography study of human patients, we examined this question by studying spatial patterns of activity (broadband gamma power) that emerge during sleep (sleep patterns) and comparing them to the functional organization of sensory cortex that is activated by naturalistic stimuli during the awake state. Our results show a high correlation (p < 10(-4), permutation test) between the sleep spatial patterns and the functional organization found during wakefulness. Examining how the sleep patterns changed through the night highlighted a stage-specific difference, whereby the repertoire of such patterns was significantly larger during rapid eye movement (REM) sleep compared with non-REM stages. These results reveal that intricate spatial patterns of sensory functional organization emerge in a stage-specific manner during sleep.

Selectivity of audiovisual ECoG responses revealed under naturalistic stimuli in the human cortex.

A fundamental debate in the study of cortical sensory systems concerns the scale of functional selectivity in cortical networks. Brain imaging studies have repeatedly demonstrated functional selectivity in entire cortical areas and networks using predetermined stimuli. However, it is not clear to what extent these networks are heterogeneous, i.e., whether the selectivity profiles in subregions within each sensory network show significant dissimilarity. Here, we studied local functional selectivity in the human cortex using naturalistic movie clips shown to 12 patients implanted with intracranial electrocorticography electrodes (590 in total), providing extensive cortical coverage. We examined the similarity of response profiles (40- to 80-Hz gamma-power modulations) across electrodes using a novel data driven approach without assuming any predefined category. Our results show that the functional selectivity of each highly responsive electrode was different from that of all other electrodes across the sensory cortex. Thus most responsive electrodes showed an activation profile that was unique in each patient and was similar to that of only 0.3% (1-2) of all other electrodes across all patients. Functional similarity between electrodes was linked to anatomical proximity. While in most electrodes the source of selectivity was complex, a small subset showed the well-documented selectivity to faces and actions. Our results indicate that the human sensory cortex is organized as a mosaic of functionally unique subregions in which each site manifests its own special response profile.

Spatial and object-based attention modulates broadband high-frequency responses across the human visual cortical hierarchy.

One of the puzzling aspects in the visual attention literature is the discrepancy between electrophysiological and fMRI findings: whereas fMRI studies reveal strong attentional modulation in the earliest visual areas, single-unit and local field potential studies yielded mixed results. In addition, it is not clear to what extent spatial attention effects extend from early to high-order visual areas. Here we addressed these issues using electrocorticography recordings in epileptic patients. The patients performed a task that allowed simultaneous manipulation of both spatial and object-based attention. They were presented with composite stimuli, consisting of a small object (face or house) superimposed on a large one, and in separate blocks, were instructed to attend one of the objects. We found a consistent increase in broadband high-frequency (30-90 Hz) power, but not in visual evoked potentials, associated with spatial attention starting with V1/V2 and continuing throughout the visual hierarchy. The magnitude of the attentional modulation was correlated with the spatial selectivity of each electrode and its distance from the occipital pole. Interestingly, the latency of the attentional modulation showed a significant decrease along the visual hierarchy. In addition, electrodes placed over high-order visual areas (e.g., fusiform gyrus) showed both effects of spatial and object-based attention. Overall, our results help to reconcile previous observations of discrepancy between fMRI and electrophysiology. They also imply that spatial attention effects can be found both in early and high-order visual cortical areas, in parallel with their stimulus tuning properties.

A widely distributed spectral signature of task-negative electrocorticography responses revealed during a visuomotor task in the human cortex.

While research of human cortical function has typically focused on task-related increases in neuronal activity, there is a growing interest in the complementary phenomenon-namely, task-induced reductions. Recent human BOLD fMRI studies have associated such reductions with a specific network termed the default mode network (DMN). However, detailed understanding of the spatiotemporal patterns of task-negative responses and particularly how they compare across different cortical networks is lacking. Here we examined this issue in a large-scale electrocorticography study in patients performing a demanding backward masking task. Our results uncovered rapid (<1 s) task-induced reductions in gamma power, often concomitant with power increase in alpha/beta bands. Importantly, these responses were found both in the DMN and sensory-motor networks. Comparing the task-negative responses across these different networks revealed similar spectral signatures and dynamics. We hypothesize that the task-negative responses may reflect a cortical switching mechanism whose role is to steer activity away from cortical networks, which are inappropriate for the task at hand.

Enhanced functional synchronization of medial and lateral PFC underlies internally-guided action planning.

Actions are often internally guided, reflecting our covert will and intentions. The dorsomedial prefrontal cortex, including the pre-Supplementary Motor Area (pre-SMA), has been implicated in the internally generated aspects of action planning, such as choice and intention. Yet, the mechanism by which this area interacts with other cognitive brain regions such as the dorsolateral prefrontal cortex, a central node in decision-making, is still unclear. To shed light on this mechanism, brain activity was measured via fMRI and intracranial EEG in two studies during the performance of visually cued repeated finger tapping in which the choice of finger was guided by either a presented number (external) or self-choice (internal). A functional-MRI (fMRI) study in 15 healthy participants demonstrated that the pre-SMA, compared to the SMA proper, was more active and also more functionally correlated with the dorsolateral prefrontal cortex during internally compared to externally guided action planning (p < 0.05, random effect). In a similar manner, an intracranial-EEG study in five epilepsy patients showed greater inter-regional gamma-related connectivity between electrodes situated in medial and lateral aspects of the prefrontal cortex for internally compared to externally guided actions. Although this finding was observed for groups of electrodes situated both in the pre-SMA and SMA-proper, increased intra-cluster gamma-related connectivity was only observed for the pre-SMA (sign-test, p < 0.0001). Overall our findings provide multi-scale indications for the involvement of the dorsomedial prefrontal cortex, and especially the pre-SMA, in generating internally guided motor planning. Our intracranial-EEG results further point to enhanced functional connectivity between decision-making- and motor planning aspects of the PFC, as a possible neural mechanism for internally generated action planning.

Epilepsy surgery in children compared to adults.

AIM: The purpose of this study was to compare the frequency of various surgical techniques and surgical outcome between pediatric and adult populations that underwent epilepsy surgery by the same team. METHODS: All patients who underwent epilepsy surgery at the Tel Aviv Medical Center between 1997 and 2006 and had been followed up for >2 years were eligible for this study. The majority (90%) of all epilepsy surgeries carried out in Israel were performed in this institution and by a single neurosurgeon. Only patients that underwent video-EEG monitoring as part of the presurgical evaluation were included in the study. RESULTS: A total of 186 patients (131 adults and 55 children) underwent epilepsy surgery in our institute during the study period, and follow-up was available for 177 patients (95%). While the adults underwent significantly more temporal lobe resections (51 vs. 20%, p < 0.0001), the children had significantly more extra-temporal non-lesional resections (18 vs. 1%, p < 0.0001) and hemispherectomies (5 vs. 1%, p = 0.002). Over one half (54%) of all the patients had a postoperative reduction in seizures of >90%, and 72% had a reduction of >50%, with no group difference in surgical success. Among the lesionectomies, the outcome was better for tumors, especially those in the temporal lobe. Only 1% of the patients had a long-term neurological deficit. CONCLUSIONS: Children comprised 30% of the epilepsy surgical cases during the study period. Children underwent more non-lesional resections and hemispherectomies, while adults underwent more temporal lobe resections. There was no age-related difference in surgical outcome.

Antagonistic relationship between gamma power and visual evoked potentials revealed in human visual cortex.

Scalp electroencephalography and magnetoencephalography studies have revealed a rapid evoked potential "adaptation" where one visual stimulus suppresses the event-related potential (ERP) of the second stimulus. Here, we investigated a similar effect revealed in subdural intracranial recordings in humans. Our results show that the suppression of the subdural ERP is not associated with a reduction in the gamma frequency power, considered to reflect the underlying neural activity. Furthermore, the evoked potential suppression (EPS) phenomenon was not reflected in recognition behavior of the patients. Rather, the EPS was tightly linked to the level of gamma activity preceding the event, and this effect was independent of the interstimulus time interval. Analyzing other frequency bands failed to reveal a similar link. Our results thus show a consistent antagonism between subdural ERP and gamma power although both are considered markers for neural activity. We hypothesize that the ERP suppression is due to a desynchronization of neuronal firing resulting from recurrent neural activity in the vicinity of the freshly stimulated neurons and not an attenuation of the overall neural activity.

Bilateral hippocampal lesion and a selective impairment of the ability for mental time travel.

Mental time travel allows individuals to mentally project themselves backwards and forwards in subjective time. This case report describes a young woman suddenly rendered amnesic as a result of bilateral hippocampal damage following an epileptic seizure and brain anoxia. Her neuropsychological profile was characterized by a high-average general level of cognitive functioning, selective deficit in episodic memory of past events and a significant difficulty to envisage her personal future. This case provides clinical support for the concept of mental time travel with its retrospective and prospective components and for the hippocampus being its critical neural substrate.

Neural "ignition": enhanced activation linked to perceptual awareness in human ventral stream visual cortex.

Human recognition performance is characterized by abrupt changes in perceptual states. Understanding the neuronal dynamics underlying such transitions could provide important insights into mechanisms of recognition and perceptual awareness. Here we examined patients monitored for clinical purposes with multiple subdural electrodes. The patients participated in a backward masking experiment in which pictures of various object categories were presented briefly followed by a mask. We recorded ECoG from 445 electrodes placed in 11 patients. We found a striking increase in gamma power (30-70 Hz) and evoked responses specifically associated with successful recognition. The enhanced activation occurred 150-200 ms after stimulus onset and consistently outlasted the stimulus presentation. We propose that the gamma and evoked potential activations reflect a rapid increase in recurrent neuronal activity that plays a critical role in the emergence of a recognizable visual percept in conscious awareness.

Quality of life in seizure-free patients with epilepsy on monotherapy.

Epilepsy is a multifaceted chronic disorder which has diverse and complex effects on the well-being of the patient. Although it is evident that seizure type and frequency play a critical role in the quality of life (QOL) of patients with epilepsy, it is less clear what the major determinants are that influence QOL in seizure-free patients receiving monotherapy. The aim of this study was to evaluate demographic, clinical, and socioeconomic factors influencing the QOL of seizure-free patients receiving monotherapy. All participants were patients from four medical centers who had epilepsy, were on monotherapy, and had been seizure-free for at least 1 year. Responders completed three questionnaires on demographic and clinical information, QOL, and antiepileptic drug (AED) side effects during routine follow-up visits in the epilepsy clinics. We present the data of 103 patients: 59 females (57.3%), mean age 37.75+/-13.66 years. Treatment side effects and unemployment (p<0.0001, p=0.037, respectively) were significant predictors for poor overall QOL, whereas age, gender, education, family status, comorbidity, seizure type, age of seizure onset, and epilepsy duration did not significantly affect overall QOL. There was no significant difference in side effects and QOL between patients receiving older versus newer AEDs. Ninety-four (92.2%) patients reported experiencing at least one side effect of AEDs when queried about specific symptoms, while only 11 (10.7%) patients replied affirmatively when asked whether they experienced "any" side effects. The most common side effects involved the central nervous system. In conclusion, this study reveals that the most significant factor influencing the QOL in seizure-free patients on monotherapy is AED side effects. QOL is a crucial component in the clinical care of patients with epilepsy, and physicians should take the time to ask specific questions on side effects of AEDs.