Eric Behnke

Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area

BACKGROUND The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance. METHODS We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus). RESULTS Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed. CONCLUSIONS Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.).

Electric current stimulates laughter

Speech and laughter are uniquely human. Although there is considerable information on the neuronal representation of speech, little is known about brain mechanisms of laughter. Here we report that electrical stimulation in the anterior part of the human supplementary motor area (SMA) can elicit laughter. This area is also involved in the initiation of speech and has been shown to have increased activity in people who stutter.

Comparison of seizure related amino acid release in human epileptic hippocampus versus a chronic, kainate rat model of hippocampal epilepsy

Recent microdialysis studies of excitatory and inhibitory amino acid release associated with paroxysmal hippocampal activity have found significant increases in the hippocampus of epileptic patients, but minimal or variable increases in animal models. One possible reason for the difference is that the animal models employed in these studies have not adequately reflected the pathophysiology of human epilepsy. The present study sought to verify the amino acid release reported in human epileptic hippocampus and then employs animal studies using a chronic rat model of epilepsy, in which rats exhibit spontaneous seizure activity 3 to 4 months after injection of kainic acid into the hippocampus. In agreement with earlier reports, we found increases in glutamate, aspartate and GABA during seizures in human hippocampus. In addition we found increases in taurine which have not previously been reported. The chronic rat model shows increases in the same amino acids as in the human epileptic hippocampus, both during spontaneous seizures and stimulation evoked after-discharges (ADs). In contrast, minimal increases are elicited by hippocampal stimulation in control (non-kainate injected) animals. These results correlate with the degree of mossy fiber reorganization found in the dentate gyrus of kainate rats or epileptic humans.

Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction

The neurochemical changes underlying human emotions and social behavior are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 (Hcrt-1) and melanin concentrating hormone (MCH), measured in the human amygdala. We show that Hcrt-1 levels are maximal during positive emotion, social interaction, and anger, behaviors that induce cataplexy in human narcoleptics. In contrast, MCH levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. MCH levels increase at sleep onset, consistent with a role in sleep induction, whereas Hcrt-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.

Increased Fast ripple to ripple Ratios Correlate with Reduced Hippocampal Volumes and Neuron Loss in Temporal Lobe Epilepsy Patients

Purpose: To determine whether hippocampal sclerosis might form an anatomical substrate for pathological high‐frequency oscillations in patients with temporal lobe epilepsy (TLE).

Paired pulse suppression and facilitation in human epileptogenic hippocampal formation

Paired pulse stimulation has commonly been employed to investigate changes in excitability in epileptic hippocampal tissue employing the in vitro slice preparation. We used paired pulse stimulation in the intact temporal lobe of patients with temporal lobe seizures to compare the excitability of pathways in the epileptogenic hippocampus (located in the temporal lobe in which seizures arise) with those in the non-epileptogenic hippocampus of the contralateral temporal lobe (in the hemisphere to which seizures spread). A total of 20 patients with temporal lobe seizure onsets were studied during chronic depth electrode monitoring for seizure localization. Intracranial in vivo stimulation and recording sites included the hippocampus, entorhinal cortex, subicular cortex and parahippocampal gyrus. A comparison of all hippocampal pathways located in the temporal lobe where seizures typically started (n = 37) with those in temporal lobes contralateral to seizure onset (n = 53) showed significantly greater paired pulse suppression of population post-synaptic potentials on the epileptogenic side (F(1,87) = 6.1, P < 0.01). Similarly, mean paired pulse suppression was significantly greater for epileptogenic perforant path responses than for contralateral perforant path responses (F(1,13) = 7.5, P < 0.01). In contrast, local stimulation activating intrinsic associational pathways of the epileptogenic hippocampus showed decreased paired pulse suppression in comparison to the epileptogenic perforant path. These results may be a functional consequence of the formation of abnormal recurrent inhibitory and recurrent excitatory pathways in the sclerotic hippocampus. Enhanced inhibition may be adaptive in suppressing seizures during interictal periods, while abnormal recurrent excitatory circuits in the presence of enhanced inhibition may drive the hypersynchronization of principal neurons necessary for seizure genesis.

Multi-institutional evaluation of deep brain stimulation targeting using probabilistic connectivity-based thalamic segmentation.

OBJECT Due to the lack of internal anatomical detail with traditional MR imaging, preoperative stereotactic planning for the treatment of tremor usually relies on indirect targeting based on atlas-derived coordinates. The object of this study was to preliminarily investigate the role of probabilistic tractography-based thalamic segmentation for deep brain stimulation (DBS) targeting for the treatment of tremor. METHODS Six patients undergoing bilateral implantation of DBS electrodes in the thalamus for the treatment of upper-extremity tremor were studied. All patients underwent stereotactic surgical implantation using traditional methods (based on indirect targeting methodologies and intraoperative macrostimulation findings) that were programmed for optimal efficacy, independent of tractography-based segmentations described in this report. Connectivity-based thalamic segmentations were derived by identifying with which of 7 cortical target regions each thalamic voxel had the highest probability of connectivity. The authors retrospectively analyzed the location of the optimal contact for treatment of tremor with connectivity-based thalamic segmentations. Findings from one institution (David Geffen School of Medicine at UCLA) were validated with results from 4 patients at another institution (University of Virginia Health System). RESULTS Of 12 electrodes implanted using traditional methodologies, all but one resulted in efficacious tremor control. Connectivity-based thalamic segmentation consistently revealed discrete thalamic regions having unique connectivity patterns with distinct cortical regions. Although the authors initially hypothesized that the most efficacious DBS contact for controlling tremor would colocalize with the thalamic region most highly connected with the primary motor cortex, they instead found it to highly colocalize with those thalamic voxels demonstrating a high probability of connectivity with premotor cortex (center-to-center distance: 0.36 ± 0.55 mm). In contrast to the high degree of colocalization with optimal stimulation site, the precise localization of the premotor cortex-defined thalamic region relative to the anterior and posterior commissures was highly variable. Having defined a connectivity-based target for thalamic stimulation in a cohort of patients at David Geffen School of Medicine at UCLA, the authors validated findings in 4 patients (5 electrodes) who underwent surgery at a different institution (University of Virginia Health System) by a different surgeon. CONCLUSIONS This report identifies and provides preliminary external validation of a novel means of targeting a patient-specific therapeutic thalamic target for the treatment of tremor based on individualized analysis of thalamic connectivity patterns. This novel thalamic targeting approach is based on identifying the thalamic region with the highest probability of connectivity with premotor and supplementary motor cortices. This approach may prove to be advantageous over traditional preoperative methods of indirect targeting, providing patient-specific targets that could improve the precision, efficacy, and efficiency of deep brain stimulation surgery. Prospective evaluation and development of methodologies to make these analyses more widely available to neurosurgeons are likely warranted.

Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey: Laboratory investigation

OBJECT Deep brain stimulation (DBS) has become an effective therapy for an increasing number of brain disorders. Recently demonstrated DBS of the posterior hypothalamus as a safe treatment for chronic intractable cluster headaches has drawn attention to this target, which is involved in the regulation of diverse autonomic functions and feeding behavior through complex integrative mechanisms. In this study, the authors assessed the feasibility of ventromedial hypothalamus (VMH) DBS in freely moving vervet monkeys to modulate food intake as a model for the potential treatment of eating disorders. METHODS Deep brain stimulation electrodes were bilaterally implanted into the VMH of 2 adult male vervet monkeys by using the stereotactic techniques utilized in DBS in humans. Stimulators were implanted subcutaneously on the upper back, allowing ready access to program stimulation parameters while the animal remained conscious and freely moving. In anesthetized animals, intraoperatively and 6-10 weeks postsurgery, VMH DBS parameters were selected according to minimal cardiovascular and autonomic nervous system responses. Thereafter, conscious animals were subjected to 2 cycles of VMH DBS for periods of 8 and 3 days, and food intake and behavior were monitored. Animals were then killed for histological verification of probe placement. RESULTS During VMH DBS, total food consumption increased. The 3-month bilateral implant of electrodes and subsequent periods of high-frequency VMH stimulation did not result in significant adverse behavioral effects. CONCLUSIONS This is the first study in which techniques of hypothalamic DBS in humans have been applied in freely moving nonhuman primates. Future studies can now be conducted to determine whether VMH DBS can change hypothalamic responsivity to endocrine signals associated with adiposity for long-term modulation of food intake.

Early postoperative appearance of radiofrequency lesions on magnetic resonance imaging.

Eleven patients who underwent stereotactic radiofrequency lesions in the central nervous system had magnetic resonance imaging follow-up within 72 hours of surgery to determine the early appearance of their lesions. Eight patients with severe tremor, one with chronic pain, and two with dystonia were analyzed. There were six female patients and five male patients, age 7 to 75 years (mean +/- standard deviation = 42 +/- 21). Magnetic resonance imaging was performed postoperatively at 32 +/- 25 hours (range, 3-72). Postoperative T1-weighted spin echo images demonstrated foci of iso- to hyperintensity surrounded by an edge of hypointensity, and corresponding T2-weighted images showed a lesion with three concentric zones consisting of inner hypointense, middle hyperintense, and outer hypointense zones. Gadolinium increased T1-weighted image lesion visibility, and a ring of enhancement around the zone of hypointensity was observed. Lesions could be seen as early as 3 hours after surgery. The lesions were best shown on gadolinium-enhanced T1-weighted images and on T2-weighted images. The edema surrounding the lesion increased over time, up to the 72 hours studied. These data provide important information on the development of lesion appearance, which may be applied in the development of real-time magnetic resonance imaging monitoring of radiofrequency lesion formation. This technique associated with electrophysiological response and the real-time visualization of the anatomic correlation of the probe may allow for a very precise and selected lesion in the central nervous system for the treatment of functional disorders and brain tumors.

Correlation between MRI-Based Stereotactic Thalamic Deep Brain Stimulation Electrode Placement, Macroelectrode Stimulation and Clinical Response to Tremor Control

In this study we compared the position of the electronically active contact of the thalamic (Vim) deep brain stimulation (DBS) electrode to the stereotactic location of its tip. Fifteen patients with either Parkinson’s disease (PD) or essential tremor (ET) underwent stereotactic, MRI-based placement of the Medtronic quadripolar DBS electrode. An overall improvement of 69% was achieved in the tremor scores during a period of 1–13 months after implantation of the DBS electrode. Eleven patients with ET showed 70% clinical improvement of tremor, compared to a 58% response observed in the 4 patients with PD. The electrode tip center was 11.2 ± 1.54 mm lateral to the third ventricular wall, 5.38 ± 1.02 mm anterior to the posterior commissure and 2.9 ± 3.57 mm inferior to the level of AC–PC line. The most significant deviation from the planned stereotactic target was observed in the Z-coordinate. In our group of patients, stimulation settings favored the contacts closer to the AC–PC line, correcting the electrode tip position to 0.80 ± 2.84 mm (p < 0.001) inferior to the level of the AC–PC line. In our experience, thalamic DBS offers a reversible and adjustable ‘lesion’ to compensate for the anatomic variabilities encountered in the positioning of the DBS electrode tip.