PART 1

When the amygdala is electrically stimulated, the result is often a set of behavioral and autonomic
responses which resemble a state of fear or anxiety, including increased heart rate and blood
pressure, increased respiration, ‘freezing’ behavior, and facial expressions of fear.1-3 In humans,
subjective feelings of fear or apprehension are also typically produced. These responses are
eliminated by hypothalamic lesions and by lesions of amygdala-hypothalamic pathways.2 However,
studies using chemical stimulation of the hypothalamus and the amygdala (as by micro-injection of
excitatory amino acids, which avoids simultaneous activation of fibers of passage) have indicated
that, while the amygdala-hypothalamic connections may mediate the autonomic changes, the
behavioral response is most likely medicated by projections from the amygdala to the midbrain
central gray region.3 Davis (1994)1 provides a schematic illustrating the respective contributions of
each of several hypothalamic and brainstem targets of the Amygdaloid Central Nucleus to the fear
response-- for example, amygdaloid projections to the lateral hypothalamus mediate HR and BP
responses; those to the Paribrachial Nucleus, Respiratory distress; those to the central grey, the
freezing response; and so forth. It seems that activation of the amygdala alone is sufficient to cause,
via its interaction with numerous brain regions, all of the physical and psychological manifestations
of the classic fear response2.

Amygdala lesions have been found to eliminate various measures of natural or innate fear in rats,
birds, and other species.1,2 The hypo-emotionality mentioned earlier carries over to situations in
which the animal would typically flee or exhibit defensive behavior, as demonstrated by increased
contact and ‘fearless’ exploratory behavior displayed by amygdala-lesioned rats when confronted
with a sedated cat.2 Inhibited adrenocortical responses to olfactory or sciatic nerve stimulation,
attenuated ulceration from restraint stress, and reduced hypertension from high noise levels have
also been observed. However, some data is less straightforward—e.g., measures of neophobia do
not appear to be consistently affected by amygdala lesions as might be anticipated.1

There is ample evidence to suggest that, aside from mediating innate fear, the amygdala is also
crucial for attaching affective significance to fear-conditioned stimuli—that is, to previously-neutral
stimuli temporally paired with aversive events.3,4 A stimuli, when so conditioned, alters neural firing
in the amygdala, and lesions of the amygdala can attenuate or eliminate HR and BP increases,
freezing, and other responses to aversively- conditioned stimuli.2 Moreover, such emotional
associations established through the amygdala are highly resistant to extinction and forgetting;3 it
would seem challenging to re-assign emotional valance to stimuli once established, again
manifesting an adaptive advantage.

PART 2

Here, we report the results of a two-year, randomized, double-blind, placebo-controlled, Phase III
Clinical trial of Drug X in patients with relapsing multiple sclerosis. Five hundred eighty-four patients
were randomly assigned to receive Drug X (at a dose of 20 mg/ml) and 294 to receive placebo by
intravenous infusion every eight weeks for 24 months. The primary endpoint was the rate of clinical
relapse at 12 months; critical secondary endpoints included the rate of clinical relapse at 24 months;
the number of new or enlarging hyperintense lesions as detected by T2- Weighted magnetic
resonance imaging (MRI) at 12 and 24 months; and the rate of sustained progression of disability as
measured by the Expanded Disability Status Scale (EDDS) at 12 and 24 months.
Drug X was found to reduce the rate of clinical relapse at 12 months by 68.1% (p<0.001 vs. placebo)
and at 24 months by 62% (p=0.015 vs. placebo) and led to an 82% reduction in the accumulation of
new or enlarging hyperintense MRI Lesions over two years (mean numbers of lesions: 1.9 with Drug
X and 11.0 With placebo; p<.05). Drug X reduced disability progression as measured by EDDS by 42.3
percent over two years (hazard ratio, 0.58; 95 percent confidence interval (CI), 0.43 to
0.77;p=0.048). The cumulative probability of progression (based on Kaplan-Meier analysis) was 88%
in the group receiving Drug X and 24% in the placebo group.

The adverse events that were reported at a rate of >10% in the Drug X arm and significantly more
frequently than in the placebo arm were nausea (28% vs. 22%), fatigue (26% vs. 18%), elevated liver
transaminases (15% vs. 6%) And allergic reaction (11% vs. 3%). Hypersensitivity reactions occurred in
31 patients receiving Drug X (3%), with severe hypersensitivity reactions occurring in 10 patients
(2%).