Carlo Schaller

Human memory formation is accompanied by rhinal–hippocampal coupling and decoupling

In humans, distinct processes within the hippocampus and rhinal cortex support declarative memory formation. But do these medial temporal lobe (MTL) substructures directly cooperate in encoding new memories? Phase synchronization of gamma-band electroencephalogram (EEG) oscillations (around 40 Hz) is a general mechanism of transiently connecting neural assemblies. We recorded depth-EEG from within the MTL of epilepsy patients performing a memorization task. Successful as opposed to unsuccessful memory formation was accompanied by an initial elevation of rhinal–hippocampal gamma synchronization followed by a later desynchronization, suggesting that effective declarative memory formation is accompanied by a direct and temporarily limited cooperation between both MTL substructures.

Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy

PURPOSE To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.

Neuronal substrates of sensory gating within the human brain

BACKGROUND For the human brain, habituation to irrelevant sensory input is an important function whose failure is associated with behavioral disturbances. Sensory gating can be studied by recording the brains electrical responses to repeated clicks: the P50 potential is normally reduced to the second of two paired clicks but not in schizophrenia patients. To identify its neural correlates, we recorded electrical traces of sensory gating directly from the human hippocampus and neocortex. METHODS Intracranial evoked potentials were recorded using hippocampal depth electrodes and subdural strip and grid electrodes in 32 epilepsy patients undergoing invasive presurgical evaluation. RESULTS We found evidence of sensory gating only in the hippocampus, the temporo-parietal region (Brodmanns areas 22 and 2), and the prefrontal cortex (Brodmanns areas 6 and 24); however, whereas neocortical habituating responses to paired clicks were peaking around 50 msec, responses within the hippocampus proper had a latency of about 250 msec. CONCLUSIONS Consistent with data from animal studies, our findings show that the hippocampus proper contributes to sensory gating, albeit during a time window following neocortical habituation processes. Thus, sensory gating may be a multistep process, with an early phase subserved by the temporo-parietal and prefrontal cortex and a later phase mediated by the hippocampus.

Rhinal-hippocampal theta coherence during declarative memory formation: interaction with gamma synchronization?

The hippocampus and the rhinal cortex, two substructures of the medial temporal lobe, together play a crucial role in human declarative memory formation. To investigate in detail the mechanism connecting these two structures transiently during memory formation we recorded depth EEG in epilepsy patients from within the hippocampus and the rhinal cortex. During this recording, patients performed a single‐trial word list‐learning paradigm with a free recall memory test following a distraction task. Rhinal–hippocampal EEG coherence and spectral power at both locations in the time interval up to 2 s after onset of word presentation were analysed in the frequency range 1–19 Hz. Successful as opposed to unsuccessful memory formation was associated with a general rhinal–hippocampal coherence enhancement, but without alterations in spectral power. Coherence increases in the theta range were correlated with the previously reported memory‐related changes in rhinal–hippocampal gamma phase synchronization. This correlation may suggest an interaction of the two mechanisms during declarative memory formation. While theta coherence might be associated with slowly modulated coupling related to an encoding state, rhinal–hippocampal gamma synchronization may be more closely related to actual memory processes by enabling fast coupling and decoupling of the two structures.

Primary central nervous system lymphomas are derived from germinal-center B cells and show a preferential usage of the V4-34 gene segment

Primary central nervous system lymphomas (PCNSLs) have recently received considerable clinical attention due to their increasing incidence. To clarify the histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors exhibited clonal IgH gene rearrangements. Of the 10 cases, 5 used the V4-34 gene segment, and all of these lymphomas shared an amino acid exchange from glycine to aspartate due to a mutation in the first codon of the complementarity-determining region 1. No preferential usage of D(H), J(H), V(kappa), J(kappa), V(lambda), or J(lambda) gene segments was observed. All potentially functional rearrangements exhibited somatic mutations. The pattern of somatic mutations indicated selection of the tumor cells (or their precursors) for expression of a functional antibody. Mean mutation frequencies of 13. 2% and 8.3% were detected for the heavy and light chains, respectively, thereby exceeding other lymphoma entities. Cloning experiments of three tumors showed ongoing mutation in at least one case. These data suggest that PCNSLs are derived from highly mutated germinal-center B cells. The frequent usage of the V4-34 gene and the presence of a shared replacement mutation may indicate that the tumor precursors recognized a shared (super) antigen.

Neural Bases of Cognitive ERPs: More than Phase Reset

Up to now, two conflicting theories have tried to explain the genesis of averaged event-related potentials (ERPs): Whereas one hypothesis claims that ERPs originate from an event-related activation of neural assemblies distinct from background dynamics, the other hypothesis states that ERPs are produced by phase resetting of ongoing oscillatory activity. So far, this question has only been addressed for early ERP components. Late ERP components, however, are generally thought to represent superimposed activities of several anatomically distinct brain areas. Thus, the question of which mechanism underlies the genesis of late ERP components cannot be easily answered based on scalp recordings. In contrast, two well-investigated late ERP components recorded invasively from within the human medial temporal lobe (MTL) in epilepsy patients, the so-called MTL-P300 and the anterior MTL-N400 (AMTL-N400), are based on single source activity. Hence, we investigated whether the MTL-P300 and the AMTL-N400 are based on an event-related activity increase, a phase reset of ongoing oscillatory activity or both. ERPs were recorded from the hippocampus and rhinal cortex in subjects performing a visual oddball paradigm and a visual word recognition paradigm. With wavelet techniques, stimulus-related phase-locking and power changes were analyzed in a frequency range covering 2 to 48 Hz. We found that the MTLP300 is accompanied by both phase reset and power increase and that both effects overlap partly in time. In contrast, the AMTL-N400 is initially associated with phase locking without power increase and only later during the course of the AMTL-N400 we observed an additional power increase. In conclusion, both aspects, event-related activation of neural assemblies and phase resetting of ongoing activity seem to be involved in the generation of late ERP components as recorded in cognitive tasks. Therefore, separate analysis of event-related power and phase-locking changes might reveal specific insights into the mechanisms underlying different cognitive functions.

Microsurgical Results for Small Arteriovenous Malformations Accessible for Radiosurgical or Embolization Treatment

OBJECTIVE A consecutive series of microsurgically treated small arteriovenous malformations (AVMs), up to 3 cm in diameter, which are theoretically ideal candidates for radiosurgery or embolization, is described. We intended to elucidate the safety and efficacy of the microsurgical removal of AVMs, as compared with the results for radiosurgery and embolization reported in the literature. METHODS Sixty-two patients (32 female and 30 male patients) ranging in age from 7 to 72 years (mean age, 33.3 yr) were included in the series. Of these, 46.8% presented with intracerebral hemorrhage and 24.2% presented with seizures. The 62 patients underwent microsurgical removal of their small (<3 cm) cerebral AVMs by the same surgeon. Twenty-six AVMs (41.9%) were assigned Spetzler-Martin Grade I, 24 (38.7%) were assigned Grade II, and 12 (19.4%) were assigned Grade III. Thirty-three AVMs (53.2%) were located in eloquent brain regions. All patients underwent postoperative control angiography and clinical follow-up after 3 and 6 months. RESULTS The AVMs were extirpated, as confirmed by angiography, in all except one patient, thereby accounting for a 98.4% success rate per angiographic findings. The rate of immediate new postoperative neurological deficits or worsening of preexisting neurological deficits was 27.4%, and the rate of permanent significant neurological deficits was 3.2% at late follow-up. The rate of permanent significant deficits occurring after the microsurgical removal of small AVMs in eloquent regions was 6.1%. The mortality rate in the reported series was 0%. The surgical morbidity rate was 9.7%. CONCLUSION Microsurgery for small AVMs is superior to radiosurgery or interventional neuroradiology because of its high rate of efficacy and low rate of permanent morbidity and because immediate cure of the AVMs can be achieved in the vast majority of patients. The place for radiosurgery in the treatment of small AVMs needs to be more sharply defined after careful assessment of relevant cases by an experienced vascular neurosurgeon.

Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator.

We have tested a treatment protocol for intracerebral hemorrhage (ICH), consisting of stereotactic insertion of a catheter into the clot, hematoma lysis by the injection of a fibrinolytic agent, recombinant tissue-plasminogen activator (rt-PA), and closed system drainage of the liquefied clot. Fourteen patients underwent computed tomographically guided stereotactic hematoma puncture and silicone tube insertion within 72 hours of intracerebral hemorrhage. The majority (nine patients) suffered from ganglionic ICH, and the size of the hematoma ranged between 3 x 3 x 4 cm and 7 x 7 x 4 cm (mean, 5.2 x 4 x 3.6 cm). All patients had major neurological deficits with or without an impaired level of consciousness, but without signs of transtentorial herniation. The initial, then daily, dose (in milligrams) of rt-PA administered via the silicone tube equalled the maximal diameter (in centimeters) of the original and remaining clot as measured initially, then daily, by computed tomographic scan. The number of rt-PA injections was four in one patient, three in eight patients, two in four patients, and one in one patient, and the total dose of rt-PA required ranged from 5 to 16 mg (mean, 9.9 mg). After rt-PA injection, the tubing was clamped for 2 hours and then opened to drain spontaneously through a closed system against 0 cm of pressure. At follow-up 6.6 months (mean) after treatment (ranging from 3 to 13 months) and according to the Glasgow outcome score, one patient was Grade V, four were Grade IV, five were Grade III, two were Grade II, and two had died.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage.

A prospective series of 20 patients with moderate to severe intraventricular haemorrhage (IVH) was studied for the effect of intraventricular administration of recombinant tissue plasminogen activator (rt-PA) on reduction of haematoma volume and prognosis. On the day of haemorrhage ventriculostomy was performed and 2 to 5 mg of rt-PA were injected via the external ventricular drainage, followed by drainage closure for two hours. In 14 patients rt-PA treatment was repeated. Computed tomography showed complete clot lysis or substantial reduction of intraventricular haematoma volume in 19 patients within 96 hours; the clearance of the third and fourth ventricle preceded the clearance of the lateral ventricles. Decrease of ventricular enlargement was seen in all but one patient with initial ventricular dilatation. Increase of haematoma volume and ventricular size was found in one patient. Outcome was minor or no neurological deficit in nine patients, disabling neurological deficit in six patients, and vegetative status in four patients. One patient did not survive the IVH. Intraventricular treatment with rt-PA seems effective in rapid lysis of intraventricular haematoma and normalisation of impaired CSF circulation. This treatment may contribute to an improvement in prognosis of moderate to severe IVH.

Digital photography and 3D MRI-based multimodal imaging for individualized planning of resective neocortical epilepsy surgery

Summary:  Purpose: Invasive presurgical work up of pharmacoresistant epilepsies presumes integration of multiple diagnostic modalities into a comprehensive picture of seizure onset and eloquent brain areas. During resection, reliable transfer of evaluation results to the patients individual anatomy must be made. We investigated the value of digital photography–based grid localization in combination with preoperative three‐dimensional (3D) magnetic resonance imaging (MRI) for clinical routine.