Neurochemical determinants of fast EEG oscillations

A basic question in functional brain research is how the manifold of serial and
parallel neuronal activations needed to process basic stimuli are integrated
and bound together. The precise timing and integration of neural activation is
crucial for successful information processing in the brain. This is known as
the
*binding problem*. Several studies have suggested an important role for high
frequency or Gamma Band activity (30 - 100 Hz) in the binding and
integration process of neuronal networks in the brain. Gamma band activity can
be measured in different paradigms. One is during ongoing cognitive activity.
It has been shown that gamma band activity can be measured in relatively simple
tasks; movie watching, music listening, story listening.
Patients with Alzheimer*s disease (AD) show impaired performance in
tasks that require transfer of information from different locations in the
brain. A
review by suggested that the neuropsychological impairment in AD is consistent
with a syndrome of disconnection. Several studies have reported decreased gamma
band
synchonisation in AD. The decrease of gamma band synchronization in AD has been
considered as a measure of functional disconnection. In a previous study we
demonstrated increased gamma band power during music listening, story listening
and movie watching, in AD when compared to Mild Cognitive Impairment (MCI)
patients and healthy controls. In this study we analysed induced
gamma band power, which is considered to reflect perceptual processing of
the stimuli.
We furthermore demonstrated that induced gamma band power has a high
test-retest reliability in patient groups and that the gamma band power
correlated to cognitive performance. An explanation for our findings increased
gamma band power in AD reflects compensation for synaptic disconnection in
AD. Another explanation is that there is a change in function of the
neurotransmitters that normally generate and regulate the gamma band.
Acetylcholine, glutamate and GABA are know regulators of the gamma and
are changes in function in AD. To evaluate the role of glutamate and GABA in
induced gamma band activity, we will repeat our earlier experiment in healthy
subjects.
In this study memantine and lorazepam will be used to alter GABA and
glutamate function. Memantine is a NMDA receptor antagonist, which is used
to reduce neurotoxic glutamatergic activity in AD. Memantine earlier showed
to reduce memory performance in healthy subjects.
Lorazepam is a GABA agonist which is common used as an anxiolytic drug.
Hypothesis
Blockade of Glutamatergic neurotransmission by the administration of Memantine
will results in decreased gamma band power and synchronization.
Stimulation of GABA-ergic neurotransmission will have no effect on
synchronization but will decrease gamma band power. On behavioral tasks it is
to be expected that both memantine and lorazepam produce cognitive impairment.

Rationale
Since gamma band activity is thought to be an important mechanism in perceptual
binding and cognitive function, interest in changes in gamma band activity in
neuropsychiatric disorders has grown rapidly. Changes in gamma band
oscillations have been shown in a variety of cognitive disorders (Herrmann &
Demiralp, 2005). Knowledge on the pharmacological constituents of the gamma
band is necessary to be able to use gamma band oscillations as a biomarker in
clinical studies or as an endpoint in therapeutical trails. There is evidence
that there is an important role for GABA and glutamate in the generation and
regulation of the gamma band. Most evidence comes from animal studies and
there is little knowledge on how the induced gamma band is regulated in humans.
Memantine and lorazepam will be used to alter the GABA-ergic and glutamergic
neurotransmission, to evaluate their role in the generation and modulation of
the gamma band.

Objectives
• To determine whether induced gamma band power decreases after Memantine
compared to Lorazepam and placebo condition.
• To determine whether induced gamma band power increases after Lorazepam
• To determine whether 40 Hz SSR decreases after Memantine, compared to
Lorazepam and placebo condition.
• To determine whether 40 Hz SSR increases after Lorazepam, compared to
Memantine and placebo condition.
• To determine the effects of Lorazepam and Memantine on synchronization of the
40 Hz SSR.
• To determine the effects of Lorazepam and Memantine on synchronization of
induced gamma band.

The study will be conducted according to a double blind, 3-way crossover
design. Treatments will be single oral doses of memantine 30 mg, lorazepam 1 mg
and placebo. Balancing of treatments will be accomplished by
block-randomization using six treatment orders residing in two 3x3 Latin
squares. The minimum washout period between treatments will be 7 days.

Memantine a NMDA recptor antagonst and Lorazepam, a GABA agonsist and a placebo
will be adminsitered to the participants on tree seperape occasions.

The burden for the subjects will be the three testing days, which take 7 hours
and might be experienced long and intensive. The EEG paradigms have been
used earlier in a study with Alzheimer patients. These Alzheimer patients
were able to perform these test without much burden. It is therefore to be
expected that these patients are able to perform these test without trouble.
The medication used might evoke adverse effects. Earlier publications
reported mild adverse effects of memantine and lorazepam. The risks in
participating in this study are very low.
The aim of this study is to provide more knowledge on the involvement
GABA and glutamate in the regulation gamma band oscillations. These
findings are relevant for the evaluation of gamma band changes as a marker
of cognitive function.