Mania & Manic Depression

MANIA & MANIC DEPRESSION

From:
Neuropsychiatry, Neuropsychology, Clinical Neuroscience (Lippincott, Williams
& Wilkins)

by Rhawn Joseph, Ph.D.

Mania is not uncommon, at least initially, following right frontal lobe injuries (particularly in males). By contrast, mania in females, has been associated with abnormalities in the amygdala, temporal lobe, right frontal lobe, and the head of he caudate nucleus.

Patients with mania may
rapidly altnerate between moods, being happy and giving one moment, and then
enraged and accusatory the next. They may believe themselves to be the richest
man or woman in the world, and the next accuse themselves of the most horrible
crimes against humanity. Hence, in addition to the development of delusions,
patients with mania may also display waxing and waning moods, and thus
alternate between depression and mania.

In this regard it is
noteworthy that whereas damage to the right frontal lobe is associated with
mania, injuries to the left frontal lobe are associated with depression.
MANIC-DEPRESSION

FRONTAL LOBE DEPRESSION

Depression is often a
realistic reaction to injury or death, or other misfortunes. In order to become
realistically depressed also requires the cognitive capacity to appreciate and
thus feel depressed about the sad nature of the circumstances that they are
confronted with. In consequence, that area of the brain mediating the
depression may become excessively active, whereas yet another region of the
cerebrum which is expressing the depression may become underactive.

In general, left frontal
injuries are associated with tearfulness, irritability, and depression.
Psychiatric patients classified as depressed, and normal individuals made to
feel severely depressed, demonstrate insufficient left frontal activation and
arousal (d’Elia and Perris 1973, Perris 1974; Tucker et al. 1981).

Patients who are
severely depressed demonstrate insufficient activation and a significant lower
integrated amplitude of the EEG evoked response over the left vs right frontal
lobe (d’Elia and Perris 1973, Perris 1974). With recovery the amplitude of the
evoked response increases to normal left hemisphere levels–as is also the case
as demonstrated in functional imaging studies (Bench et al., 1995).

TEMPORAL LOBES &
MANIC-DEPRESSION

Personality, emotional,
mood, and sexual disturbances are a frequent complication of temporal lobe
abnormalities. Such individuals may develop paranoid, hysterical, or depressive
tendencies, deepening of mood, hyposexuality and other characteristics
suggestive of affective disorders (Bear et al. 1982; Gibbs, 1951; Gloor 1986,
1992, 1997; Herman & Chambria, 1980; Strauss et al. 1982; Williams, 1956).
Unfortunately, a potential side effect of temporal lobe disturbances is the
development of kindling, and perhaps seizure activity.

Be it kindling,
sub-clinical seizure activity, or the development of temporal lobe epilepsy, as
abnormal activity levels wax and wane, personality, emotion and mood may be
effected accordingly (e.g. Herman & Chambria, 1980; Strauss et al., 1982;
Trimble 1991; Williams, 1956). For example, a depressive aura may precede and
thus hearld the coming of a seizure by hours or even days. Depression (lasting
from hours to weeks) may also occur as an immediate sequela to the seizure
(Trimble 1991; Williams, 1956).

Perceptions and
impressions, as well as thought and language formation may become infected with
depressive and manic impulses and abnormally invested with emotional, paranoid,
and even religious significance. Patients may appear labile, delusional, or
paranoid or wracked by religious guilt and feelings of persecution. Again, such
patients may claim to be the most terrible person on Earth and express a depressive-related
fear that they are in some way responsible for certain specified or unspecified
ills that they perceive as afflicting the world. Moreover, they may not only
feel depressed and responsible, but fearful of retribution for the wrongs they
have committed. Yet, in this regard, their delusions are exceedingly grandiose
and thus represent the manic aspects of the illness.

Because abnormal
temporal lobe activity may wax and wane, and as various transmitters such as
norepinephrine and serotonin may also wax, wane, and rebound, patients may also
display labile and manic-like abnormalities. That is, they may easily cry,
becoming angry and accusatory, and later feel more or less elated, and/or
become convinced that they must take some action to save the world.

For example, because
religious ideation may be triggered by temporal lobe and amygdala
hyperactivation (see chapter 9), patients may come to believe that they have
taken up the sins of the world (e.g. messiah complex) and that it is up to them
to act at the behest of God. Because the amygdala is interconnected with
Wernicke’s area and the inferior parietal lobe, they may therefore
“preach” and write out their psychotic religious beliefs. Moreover,
because the amygdala maintains rich interconnections with the basal ganglia, as
well as the frontal lobes and reticular formation, they may suddenly feel
exceeding energized and aroused and motorically attempt to act out their
delusional thoughts and feelings in a hyperactivated fashion. A diagnosis of manic-depression
would therefore be likely.

Although in general left
temporal lobe abnormalities are more likely to result in psychotic-affective
disorders, depression and disorganized mood states are just as likely with
right temporal lobe dysfunction (e.g. Flor-Henry, 1969, 1983; Offen, Davidoff,
Troost, & Richey, 1976; Joseph, 1988a; Sherwin, 1981; Schiff et al., 1982;
Taylor, 1975; Weil, 1956; see also chapters 3 & 4). Moreover, in that the
right and left temporal lobes are interconnected via the corpus callosum, as
well as via the anterior commissure, it is likely that abnormalities in one
temporal lobe may well effect the functional integrity of the other.

It is noteworthy,
however, that among those with left temporal lobe damage, that these patients
are more likely than those with right sided lesions to also complain of thought
blocking, and feelings of emptiness: “feelings don’t reach me
anymore” (Weil, 1956). Presumably this is a consequence of limbic
disconnection. That is, the seizure foci (or lesion) acts to deconnect the
limbic areas, such as the amygdala, from the temporal (or orbital frontal)
lobes. In consequence, percepts and thoughts no longer come to be assigned
emotional or motivational significance.

RIGHT FRONTAL/TEMPORAL
LOBE MANIA

As reviewed above, mania
may be induced by damage or dysfunction involving the right frontal lobe,
and/or the amygdala/temporal lobe. With predominant amygdala (and temporal
lobe) dysfunction, individuals may appear labile, delusional, psychotic, and
display what has been variably referred to as manic-depression, or bipolar
affective disorder coupled with disorganized thinking, ideas of reference,
sleep and appetite disorders, inappropriate sexual activity, including, in some
instances, hyper-religiousness and related delusions.

Mania in the absence of
severe depression appears to be far more likely with right temporal, and in
particular, right frontal lesions -especially in men (Joseph 1986a, 1988a;
1999a). Given the dominant role of the frontal lobes, and the right frontal
lobe in particular, in the control and regulation of arousal (chapter 19) it is
perhaps not surprising that injuries involving this tissue may result in a loss
of control over arousal. Moreover, as the right frontal lobe appears to exert
bilateral influences on cerebral activation and inhibition, it is also this
portion of the brain that when damaged is the most likely to produce
activational disturbances including mania.

In addition, since the
right hemisphere is dominant in the perception and expression of facial,
somesthetic and auditory emotionality, damage to this half of the brain can
result in a variety of affective and social-emotional abnormalities including
lability, florid manic excitement, pressured speech, bizzare confabulatory responding,
childishness, irritability, euphoria, impulsivity, promiscuity and abnormal
sexual behavior (Bear, 1977, 1983; Bear & Fedio, 1977; Clark & Davison,
1987; M. Cohen & Niska, 1980; Cummings & Mendez, 1984; Erickson, 1945;
Forrest, 1982; Gardner et al., 1983; Gruzelier & Manchanda, 1982; House et
al. 1990; Jamieson & Wells, 1979; Jampala & Abrams, 1983; Joseph,
1986a,1990d; Lishman, 1968; Offen et al. 1976; Rosenbaum & Berry, 1975;
Spencer et al. 1983; Spreen et al., 1965; Starkstein et al. 1987; Stern &
Dancy, 1942).

Individuals so affected
are likely to be viewed as suffering from mania.

For example, M. Cohen
and Niska (1980) report an individual with a subarachnoid hemorrhage and right
temporal hematoma who developed an irritable mood; shortened sleep time; loud,
grandiose, tangential speech; flight of ideas; and lability and who engaged in
the buying of expensive commodities. Similarly, Oppler (1950) documented an
individual with a good premorbid history who began to deteriorate over many
years’ time. Eventually, the patient developed flight of ideas, emotional
elation, increased activity, hypomanic behavior, lability, extreme fearfulness,
distractability, jocularity, and argumentativeness. The patient was also overly
talkative and produced a great deal of tangential-circumstantial ideation with
fears of persecution and delusions. Eventually a tumor was discovered (which
weighed over 74 grams) and removed from the right frontal-parietal area.

One patient, formerly
very reserved, quiet, conservative, and dignified with more than 20 patents to
his name, and who had been married to the same woman for over 25 years, began
patronizing up to 4 different prostitutes a day and continued this activity for
months. He left his job, began thinking up and attempting to act upon
extravagant, grandiose schemes, and camped out at Disneyland and attempted to
convince personnel there to finance his ideas for developing an amusement park
on top of a mountain. At night he frequently had dreams in which either John F.
or Robert Kennedy would appear and offer him advice –and he was a Republican!

Confabulation,
hypersexuality, tagentiality, and manic like behaviors seem to be more
frequently associated with right frontal dysfunction (Joseph, 1986a; 1988a,
1999a), particularly among men. Hence, when the right (or both) frontal lobes
are severely it is not uncommon for those afflicted to behave in an
inappropriate, labile, and disinhibited fashion. Individuals may become
hyperactive, distractable, hypersexual, tangential, and confabulatory and
behave in a childish, impulsive, euphoric manner (e.g. Lishman, 1968). And, it
is just as likely for such individuals to just as suddenly cease their antics
and to become largely unresponsive and seemingly disinterested in their environment
until provoked, sometimes by seemingly inconsequential and trivial stimuli.

Although men are
probably more likely than women to develop mania with right frontal lesions,
females may be similarly affected, particularly if both frontal lobes and the
orbital areas have been damaged. In one case, for example, a woman of 46 was
admitted to the hospital and observed to be careless about her person and room,
incontinent of urine and feces, to sleep very little and to act in a
hypersexual manner. Her symptoms had developed several months earlier when she
began accusing a neighbor of taking things she had misplaced and on other
occasions stripping in front of him. She began going about in just her
nightdress, informing people she was descended from queens, was very rich, and
that many men wanted to divorce their wives and marry her. During her
hospitalization she was frequently quite loud, disoriented to time and place,
and extremely tangential, jumping from subject to subject. Eventually a
meningioma involving the orbital surface of her frontal lobes was discovered
(Girgis, 1971).

As noted, although
laughing and joking one moment, these same patients can quickly become
apathetic and disinterested and/or irritated, angered, enraged, destructive, or
conversely tearful with slight provocation. Presumably, patients with right
frontal injury are more likely to produce not only manic-like behaviors but
delusional and confabulatory speech due to disinhibition and the flooding of
the speech areas with ideas that are normally filtered out (Joseph 1986a,
1988a). Right frontal injuries are also more likely to mimic orbital injuries
including the loss of regulatory restraint over limbic and thus emotional as
well as motivational functioning. Patients may not only talk too much, but eat
and drink too much, as well as behave in a socially and emotionally
inappropriate manner. Because these brain structures perform specific
functions, damage involving certain regions of the brain are more likely to give
rise to specific psychiatric symptoms as compared to damage to a different
portion of the brain. For example, mania is not uncommon, at least initially,
following right frontal injuries (particularly in males), whereas left frontal
injuries are more likely to produce negative symptoms such as blunted forms of
schizophrenia and apathetic depression (Joseph, 1999a). More emotional
affective disorders, such as depression with suicidal idea or feelings of
guilt, or so called “positive” schizophrenia, are associated with
left and right temporal lobe injuries.

In previous chapters,
the symptoms associated with injuries to particular regions and lobes of the
brain were detailed. The purpose of this chapter is to provide basically the
same data, but from a sympomatic perspective. That is, rather than discussing
the symptoms associated with, for example, frontal lobe injury, instead
depression will be presented, and then those areas of the brain which when
injured give rise to depressive symptomology, will be discussed. Hence, this
chapter provides an overview and summary of those findings which are scattered
throughout the different chapters of this text. Specifically, the different
neuroanatomical regions linked to specific psychiatric disorders will be reviewed
with an emphasis on functional localization and differences in symptomology.
Neurochemical contributions to some forms of depression and psychosis will also
be briefly reviewed.

DEPRESSION

FRONTAL LOBE DEPRESSION
Depression is often a realistic reaction to injury or death, or other
misfortunes. In order to become realistically depressed also requires the
cognitive capacity to appreciate and thus feel depressed about the sad nature
of the circumstances that they are confronted with. In consequence, that area
of the brain mediating the depression may become excessively active, whereas
yet another region of the cerebrum which is expressing the depression may
become underactive.

In general, it has been
found that the right frontal lobe demonstrated increased activity in response
to negative moods (Rauch et al., 1996; Shin et al., 1997, 1999; Teasdale et
al., 1999) whereas left frontal activity decreases (Bench et al., 1995). In
fact, repetitive transcranial magnetic stimulation of the right frontal lobe
reduces depressive symptoms (Klein et al., 1999), whereas left frontal activity
increase with the alleviation of depression as demonstrated through functional
imaging studies (Bench et al., 1995).

Not only reductions in
left frontal activity, but injuries to the left frontal lobe have been
consistently associated with depression, “psycho-motor” retardation,
apathy, irritability, and blunted mental functioning. For example, when Broca’s
area has been injured, patients not only have difficulty with expressive speech
(Bastiaanse 1995; Goodglass and Kaplan 1999; Haarmann and Kolk 1994; Hofstede
and Kolk 1994; Sarno, 1998) but they typically become exceedingly frustrated,
irritable, and depressed (Gainnoti 1972; Robinson and Benson 1981; Robinson and
Szetela 1981; Robinson and Downhill 1996). Indeed, these patients are typically
painfully aware of their deficit and thus become realistically depressed
(Gainotti 1972; Joseph, 1988a). In fact those with the smallest frontal
convexity lesions often become the most depressed (Robinson and Benson 1981).
Depression in these cases appears to be a normal reaction and as such is
mediated by undamaged tissue; i.e., the right frontal and right temporal lobe.
That is, the right hemisphere being emotionally astute, reacts appropriately to
the patient’s condition and becomes depressed.

Not only are left
frontal injuries associated with tearfulness, irritability, and depression, but
psychiatric patients classified as depressed, and normal individuals made to
feel severely depressed, demonstrate insufficient left frontal activation and
arousal (d’Elia and Perris 1973, Perris 1974; Tucker et al. 1981). For example,
reduced bioelectric arousal over the left frontal region has been reported
following depressive mood induction (Tucker et al. 1981). Similarly depressed
mothers and depressed children show reduced left relative to right frontal
activation (reviewed in Dawson 1994). With recovery from depression left
hemisphere arousal returns to normal levels.

Likewise, patients who
are severely depressed have been shown to demonstrate insufficient activation
and a significant lower integrated amplitude of the EEG evoked response over
the left vs right frontal lobe (d’Elia and Perris 1973, Perris 1974). Based on
EEG and clinical observation, d’Elia and Perris have argued that the
involvement of the left hemisphere is proportional to the degree of depression.
Moreover, with recovery the amplitude of the evoked response increases to
normal left hemisphere levels–as is also the case as demonstrated in
functional imaging studies (Bench et al., 1995).

Left frontal lobe
depression is therefore seen in those who are aphasic, and those whose
depression has been long standing or even recently provoked. The more severe
the depression, the greater is the reduction in left frontal functioning
(whereas with mild transient sadness there might be a reduction in right
frontal activity). Hence, with massive left frontal dysfunction, including even
when Broca’s area is spared, patient may become exceeding depressed, apathetic
, hypoactive and indifferent (Robinson et al. 1984; Robinson and Szetela 1981;
Sinyour, et al. 1986). With severe injuries patients may in fact become
apathetic and emotionally blunted (Blumer and Benson 1975; Freeman and Watts
1942, 1943; Girgis 1971; Hecaen 1964; Luria 1980; Passingham 1993; Stuss and
Benson 1986; Strom-Olsen 1946). One patient who “prior to his accident
requiring amputation of the left frontal pole, had been garrulous, enjoyed
people, had many friends, was active in community affairs” and had
“true charisma… became quiet and remote, spent most of his time sitting
alone smoking, and was frequently incontinent of urine, and occasionally of
stool. He remained unconcerned and was frequently found soaking wet, calmly
sitting and smoking. When asked, he would deny illness” (Blumer and Benson
1975, p. 196).

Similarly, frontal
lobotomy, especially of the left frontal lobe can produce profound apathetic
states. “The previously busy housewife who has always been a dirt-chaser,
and who has kept her fingers perpetually busy with darning, crocheting,
knitting, and so on, sits with her hands in her lap watching the ‘snails whiz
by’. Like a child she must be told to wipe the dishes, to dust the sideboard,
to sweep the porch” and even then the patient completes only half the task
as there is no longer any interest or initiative (Freeman and Watts 1943, p.
803). In some cases the apathy is so profound that “whoever has charge of
the patient will have to pull him out of bed, otherwise he may stay there all
day. It is especially necessary since he won’t get up voluntarily even to go to
the toilet” (p. 802).

In part, depression
coupled with severe apathy secondary to frontal injuries is probably related to
damage to the interconnections with the medial region, an area which when
damaged induces hypokinetic and apathetic states (see below). However, these
latter patients are not depressed, but rather severly apathetic, indifferent,
hypoactive, and poorly motivated. When questioned, rather than worried or truly
concerned about their condition the overall picture is that of confusion,
disinterest, and blunted emotionality (Freeman & Watts, 1942: Hacaen, 1964)
i.e. there is a lack of worrisome thoughts or depressive ideation.

Hence, in part, apathetic
and depressive features may result from left frontal convexity and frontal pole
damage due to a severance of fibers which link emotional impulses (such as
those being transmitted via the orbital and medial region) with external
sources of input or cognitive activity which are transmitted to the convexity
(i.e. disconnection), impulses which are transmitted from the medial frontal
lobes to the orbital, superior, and anterior frontal lobes. Through these
interconnections, emotional impulses arising in the limbic system, can be
transmitted through the medial frontal lobes to the lateral frontal lobes,
where they then become ideas. Or conversely, neocortical cognitions may be
transmitted from the lateral neocortical surface to the medial areas where they
are integrated to again become emotional ideas.

It was the recognition
that the frontal lobes acted as a bridge between emotion and idea which led to
the wide scale use of frontal lobotomy; i.e. surgical destruction of
inter-linking fibers –a technique, which when used in the 1940s and 1950s,
often involved little more than blindly swishing a “surgical ice
pick” inside somebody’s brain!

Moreover, convexity
lesions, like medial damage, may result in a disconnection not only between
cognitive-perceptual and emotional activity, but would prevent limbic system
output from reaching the motor areas such that emotional-motivational impulses
are unable to become integrated with motor activities. The patient is thus
motorically hypo-emotionally aroused (i.e. depressed), and appears to be
demonstrating psychomotor retardation.

Just as left frontal
convexity motor damage can result in left sided apraxia (due to right
hemisphere disconnection from left parietal temporal-sequential output), the
reverse can also occur. That is, with left frontal damage, linguistic impulses
not only fail to become expressed, but emotional output from the right
hemisphere and limbic system fail to become integrated with linguistic-ideation
(i.e. thought). Ideas no longer come to be assigned emotional significance. In
the extreme the motivational impetus to even engage in thought production is
cut-off.

TEMPORAL LOBES &
DEPRESSION

Personality, emotional,
mood, and sexual disturbances are a frequent complication of temporal lobe
abnormalities. Such individuals may develop paranoid, hysterical, or depressive
tendencies, deepening of mood, hyposexuality and other characteristics
suggestive of affective disorders (Bear et al. 1982; Gibbs, 1951; Gloor 1986,
1992, 1997; Herman & Chambria, 1980; Strauss et al. 1982; Williams, 1956).
Unfortunately, a potential side effect of temporal lobe disturbances is the
development of kindling, and perhaps seizure activity.

Be it kindling,
sub-clinical seizure activity, or the development of temporal lobe epilepsy, as
abnormal activity levels wax and wane, personality, emotion and mood may be
effected accordingly (e.g. Herman & Chambria, 1980; Strauss et al., 1982;
Trimble 1991; Williams, 1956). For example, a depressive aura may precede and
thus hearld the coming of a seizure by hours or even days. Depression (lasting
from hours to weeks) may also occur as an immediate sequela to the seizure
(Trimble 1991; Williams, 1956).

In large part the
production of temporal lobe depression may be due to the rich interconnections
maintained between the amygdala and temporal lobe. That is, in many cases it is
an abnormal amygdala which produces abnormal temporal lobe seizure activity
(Gloor, 1997). Given the profound role of the amygdala in all aspects of
emotional and personality functioning, in consequence, emotional and
emotional-perceptual functioning becomes abnormal to varying degrees and
patients may appear not only depressed but perhaps psychotic.

As noted, frontal lobe
depression may be characterized by apathy and even a paucity of depressive
thoughts. By contrast, the thought processes of those with temporal lobe
depression may result becomes infected with depressive and psychotic ideation
and related impulses. The patient thinks terrible things about themselves, condemns
themselves, contemplates suicide, and so on. The contamination of language and
thought with depressive ideation is a consequence of the rich interconnections
maintained between the amygdala and the primary and secondary auditory areas
(including Wernicke’s area in the left hemisphere), as well as the visual and
somesthetic cortices. Hence, perceptual as well as thought and language
formation may become infected with depressive and psychotic impulses and
abnormally invested with emotional, paranoid, and even religious significance
(Bear et al., 1979; Gibbs, 1951; Gloor 1992; Gloor et al., 1982).

Therefore, the patient
may not only report being depressed but they may appear labile, delusional, or
paranoid or wracked by religious guilt and feelings of persecution. Again, such
patients may claim to be the most terrible person on Earth and express a
depressive-related fear that they are in some way responsible for certain
specified or unspecified ills that they perceive as afflicting the world.
Moreover, they may not only feel depressed and responsible, but fearful of
retribution for the wrongs they have committed.

In fact fear followed by
depression are the most common emotional experiences associated with abnormal
temporal lobe activity (Gloor 1992; Gloor et al., 1982; Halgren 1992; Williams,
1956). Thus some patients may fear that they are responsible for what depresses
them, and/or what depresses others and as such they may appear more paranoid
and delusional than depressed.

TEMPORAL LOBE
MANIC-DEPRESSION (Bipolar Disorder)

Because abnormal
temporal lobe activity may wax and wane, and as various transmitters such as
norepinephrine and serotonin may also wax, wane, and rebound, patients may also
display labile and manic-like abnormalities. That is, they may easily cry,
becoming angry and accusatory, and later feel more or less elated, and/or
become convinced that they must take some action to save the world.

For example, because
religious ideation may be triggered by temporal lobe and amygdala hyperactivation
(see chapter 9), patients may come to believe that they have taken up the sins
of the world (e.g. messiah complex) and that it is up to them to act at the
behest of God. Because the amygdala is interconnected with Wernicke’s area and
the inferior parietal lobe, they may therefore “preach” and write out
their psychotic religious beliefs. Moreover, because the amygdala maintains
rich interconnections with the basal ganglia, as well as the frontal lobes and
reticular formation, they may suddenly feel exceeding energized and aroused and
motorically attempt to act out their delusional thoughts and feelings in a
hyperactivated fashion. A diagnosis of manic-depression would therefore be
likely.

Although in general left
temporal lobe abnormalities are more likely to result in psychotic-affective
disorders, depression and disorganized mood states are just as likely with
right temporal lobe dysfunction (e.g. Flor-Henry, 1969, 1983; Offen, Davidoff,
Troost, & Richey, 1976; Joseph, 1988a; Sherwin, 1981; Schiff et al., 1982;
Taylor, 1975; Weil, 1956; see also chapters 3 & 4). Moreover, in that the
right and left temporal lobes are interconnected via the corpus callosum, as
well as via the anterior commissure, it is likely that abnormalities in one
temporal lobe may well effect the functional integrity of the other.

It is noteworthy,
however, that among those with left temporal lobe damage, that these patients
are more likely than those with right sided lesions to also complain of thought
blocking, and feelings of emptiness: “feelings don’t reach me
anymore” (Weil, 1956). Presumably this is a consequence of limbic
disconnection. That is, the seizure foci (or lesion) acts to deconnect the
limbic areas, such as the amygdala, from the temporal (or orbital frontal)
lobes. In consequence, percepts and thoughts no longer come to be assigned
emotional or motivational significance.

HYPOTHALAMIC DEPRESSION

A common feature of
psychotic depression is loss of appetite, sleep disorders, and an inability to
feel pleasure; or, conversely, an overwhelming sense of hopelessness and
despair. In large part, disturbances such as these can also be attributed to
amygdala/temporal lobe abnormalities as well as to the hypothalamus.

Although the amygdala is
dominant in regard to all aspects of emotion, it is dependent on the
hypothalamus and frequently acts at the behest of hypothalamic impulses and
homeostatic needs (Gloor, 1997; Joseph 1992a). Conversely, the amygdala also
exerts tremendous modulatory influences on the hypothalamus. Hence,
abnormalities involving the amygdala can influence the hypothalamus, and vice
versa. Moreover, both nuclei influence the sleep cycle, dream sleep, and even
the capacity to experience pleasure when eating (see chapter 13), and the
amygdala as well as the hypothalamus are strongly influenced and dependent on
NE and 5HT which are also directly implicated in the genesis of depression.

As detailed in chapter
13, feelings of pleasure are associated with activation of a number of diverse
limbic areas including the amygdala, cingulate, substantia nigra (a major
source of dopamine), locus coeruleus (a major source of norepinephrine), raphe
nucleus (serotonin), medial forebrain bundle, and orbital frontal lobes (Brady,
1960; Lilly, 1960; Olds & Forbes, 1981; Stein & Ray, 1959; Waraczynski
et al. 1987). The predominant locus for pleasurable feelings, however, is
within the lateral hypothalamus (Olds, 1956; Olds & Forbes, 1981).

If the lateral region is
destroyed the experience of pleasure and emotional responsiveness is almost
completely attenuated. For example, in primates, faces become blank and
expressionless, whereas if the lesion is unilateral, a marked neglect and
indifference regarding all sensory events occurring on the contralateral side
occurs (Marshall & Teitelbaum, 1974). Animals will in fact cease to eat and
will die.

In contrast, activation
of the medial hypothalamus is associated with aversive and unpleasant
sensations (Olds & Forbes, 1981). However, as the lateral and medial nuclei
exert, in part, counterbalancing influences (Joseph 1992a) abnormalities in the
lateral region (and or abnormalities associated with amygdala input) may not
only result in a loss of pleasure, but create sensations of unpleasure; which,
if prolonged would probably lead to feelings of hopelessness and despair; i.e.
severe depression.

THE SUPRACHIASMATIC
NUCLEUS & DEPRESSION

Hypothalamic depression
is associated with disturbances involving the suprachiasmatic nucleus (SCN);
e.g., Seasonal Affective Disorder (Morin 1994). In humans and other species,
the SCN is a direct recipient of retinal axons and receives indirect visual
projections from the lateral geniculate nucleus of the thalamus. Presumably the
visual system acts to synchronize the SCN to function in accordance with
seasonal and day to day variations in the light/dark ratio; which in turn is
directly associated with activation and arousal vs depressed activation and
sleep. Presumably the SCN also acts to directly influence mood and arousal by
adjusting those hormonal and neurochemical activities normally associated with
activation and high (daytime) activity. If the SCN is deprived of or unable to
effectively respond to light (or related neurotransmitters), individuals may
become depressed.

For example, the
hypothalamic-pituitary axis secretes melatonin in phase with the circadian
rhythm, and phase-delayed rhythms in plasma melatonin secretion have been
repeatedly noted in most (but not all) studies of individuals with Seasonal
Affective Disorder (reviewed in Wirz-Justice et al. 1993). This is significant
for melatonin is derived from tryptophan via serotonin and low serotonin levels
have been directly linked to depression (e.g. Van Pragg 1982). However, with
light therapy melatonin secretions return to normal and the depression may be
relieved.

The presence of absence
of light, however, may be only one factor among many effecting the SCN. For
example, disturbances in temperature perception and the 5HT system may deregulate
SCN activity, as can the process of aging (Aronson et al. 1993). In
consequence, rest vs active cycles also become abnormal, with reductions in
arousal and activity; i.e. the patient becomes depressed.

In addition, depression
and SCN abnormalities may be a consequence of emotional stress on the
hypothalamus (Chauloff 1993) as well as on the amygdala and the NE and 5HT
systems. For example, the hypothalamic-pituitary axis is tightly linked with
and in fact mediates stress induced alterations in serotonin (Chauloff 1993,
Fink, 1999); as well as norepinephrine (Swann et al. 1994) which has also been
repeatedly implicated in the genesis of depression.

THE
HYPOTHALAMUS-PITUITARY-ADRENAL AXIS

The hypothalamic,
pituitary, adrenal system (HPA) is critically involved in the adaption to
stressful changes in the external or internal environment, whereas
hyperactivity of the adrenal gland is clearly associated with major depression.
In fact, the adrenal glands have been shown to increase in size during episodes
of major depression and to then revert to normal size during remission (Rubin
et al. 1995). In part, this may be secondary to (internal or externally
induced) stress, and/or a disruption in the HPA feedback regulatory system.

For example, in response
to fear, anger, anxiety, disapointment, and even hope, the hypothalamus begins
to release corticotropin releasing factor (CRF) which activates the
andenohypophysis which begins secreting ACTH which stimulates the adrenal
cortex which secretes cortisol.

These events in turn
appear to be under the modulating influences of norepinephrine. That is, as
stress increases, NE levels decrease, which triggers the activation of the HPA
axis.

Normally, cortisol
secretion is subject to the tonic influences of NE; whereas cortisol can
indirectly reduce NE synthesis. Thus a feedback system is maintained via the
interaction of these substances (in conjuction with ACTH). Moreover, cortisol
and NE levels fluctuate in reverse, and thus maintain a reciprocal relationship
with the circadian rhythm; i.e. in oppositional fashion they increase and then
decrease throughout the day and evening.

Among certain subgroups
suffering from depression, it appears that this entire feedback regulatory
system and thus the HPA axis is disrupted (Carrol et al. 1976; Sachar et al.
1973). This results in the hypersecretion of ACTH and cortisol with a
corresponding decrease in NE; which results in NE induced depression. It was
these findings which led to the development of the Dexamethasone suppression
test over 25 years ago; i.e. individuals suffering from depression show excess
cortisol, and an increased frequency of cortisol secretory episodes (Carrol et
al. 1976; Sachar et al. 1973; Swann et al. 1994).

It is also noteworthy
that dexamethason nonsuppression rates are increased in mania; specifically
“mixed manic” states which consist of lability, grandiosity, and
lability superimposed over depression (see Swann et al. 1994). These
“mixed manic” individuals also display elevated NE levels but respond
poorly to lithium and show higher levels of cortisol during the depressed phase
of their illness (Swann et al. 1994). Nevertheless, NE and 5HT abnormalities do
not exclusively influence the hypothalamus, but also exert widespread
influences throughout the neoroaxis, especially the amygdala which may well
interact with the hypothalamus in the production of certain forms of
depression.

NEUROCHEMISTRY &
DEPRESSION

As is now well known,
major factors in the pathogenesis of depression include disturbances in the
locus coeruleus (LC)-NE and 5HT systems (Arranz et al. 1994; Delgado et al.
1994; Pandey et al. 1995); neurotransmitter systems which fuel the amygdala,
inferior temporal lobe, as well as the frontal lobes and hypothalamus. For
example, a disturbance in NE synthesis and metabolism, regardless of its cause,
will disrupt limbic and cortical functioning and arousal, reduce neuroendocrine
activity, and thus the organisms ability to mobilize its defenses in response
to stress, adverse experience, or even self-defeating thoughts. Every component
of social-affective expression will be altered, especially that related to the
experience of pleasure and reward -a condition conducive to depression.
Presumably this is also due to related abnormalities in the amygdala, inferior
temporal lobe, etc.

Similarly, when 5-HT
levels are reduced individuals may become depressed. There is also an increased
tendency to respond to non-rewarding situations (Sourbrie, 1986) and to
continue to respond regardless of punishment (Spoont, 1992). Effected
individuals may fail to avoid or may even be drawn to abusive or potentially
frightening or traumatic situations, and may seem helpless to alter their
behavior, e.g. learned helplessness (see Charney et al. 1993; Krystal 1990).
Indeed, reduced 5-HT, including abnormalities in platelet serotonin receptors,
has been repeatedly noted in the brains of those who have committed suicide and
taken their lives in a violent fashion (e.g. Brown et al. 1982; Cronwell &
Henderson 1995; Pandey et al. 1995). Presumably, in these cases associated
abnormalities in the hypothalamus (loss of pleasure) and amygdala (depression
and violent suicide) are implicated.

Although it is difficult
to classify a depressive episode or psychosis strictly in terms of an
anatomical location or biochemical abnormality, it has been known for over two
decades that there are at least two subgroups who differ in regard to
depressive symptoms and NE and 5HT activity levels (Goodwin et al. 1978; Van
Dongen 1982; Van Praag 1982), as well as a third group with bipolar disorder
who show elevated D2 dopamine receptors (Pearlson et al. 1995). For example,
those with an NE depression may behave in a more emotionally labile and
expressive manner, whereas those with a 5HT depression may demonstrate a much
more profound motor retardation coupled with social withdrawal and confusion
due to sensory overload.

Moreover, both groups
respond differently to pharmacological treatment. For example, some respond to
best to impramine which inhibits NE reuptake (thus increasing NE levels in the
synapse), whereas others react best to amitriptylline which potentiates 5HT
(Goodwin et al. 1978; Van Praag 1982) and inhibits NE reuptake. This suggests
that among some individuals NE and 5HT may simultaneously contribute to a
distinct form of depression.

It has also been argued
that reduced 5HT does not cause depression per se and is not linearly related
to the level of depression (Delgado et al. 1994). Rather 5HT may be a
predisposing factor in depression which in turn may be related to a
postsynaptic deficit in 5HT utilization or binding affinity (Arranz et al.
1994; Delgado et al. 1994). Presumably the structures most effected are the
amygdala, inferior temporal and frontal lobes, and hypothalamus, which in turn
give rise to a somewhat different symptom complex that may be broadly defined
as depression.

As per the role of
dopamine, it appears that depressed and bipolar patients who display elevations
in D2 dopamine receptors are more likely to appear psychotic than suffering
from a mood disorder (Pearlson et al. 1995). Hence, those with dopamine
abnormalities tend to more closely resemble patients with schizophrenia.

SEX DIFFERENCES &
DEPRESSION

Females are far more
likely to experience depression and depressive episodes than males (DSM IV).
Although this sex difference is no doubt related to differential stresses and
hormonal factors affecting women vs men, this may also be secondary to the that
that females are at greater risk for anterior cerebral artery dysfunction (e.g.
embolism; Hier et al. 1994) and become depressed with even subtle injuries
involving the left (and right) frontal cortices.

MANIA

RIGHT FRONTAL/TEMPORAL
LOBE MANIA

As reviewed above, mania
may be induced by damage or dysfunction involving the right frontal lobe,
and/or the amygdala/temporal lobe. With predominant amygdala (and temporal
lobe) dysfunction, individuals may appear labile, delusional, psychotic, and
display what has been variably referred to as manic-depression, or bipolar affective
disorder coupled with disorganized thinking, ideas of reference, sleep and
appetite disorders, inappropriate sexual activity, including, in some
instances, hyper-religiousness and related delusions.

Mania in the absence of
severe depression appears to be far more likely with right temporal, and in
particular, right frontal lesions -especially in men (Joseph 1986a, 1988a;
1999a). Given the dominant role of the frontal lobes, and the right frontal
lobe in particular, in the control and regulation of arousal (chapter 19) it is
perhaps not surprising that injuries involving this tissue may result in a loss
of control over arousal. Moreover, as the right frontal lobe appears to exert
bilateral influences on cerebral activation and inhibition, it is also this
portion of the brain that when damaged is the most likely to produce
activational disturbances including mania.

INSERT FIGURE 1 ABOUT
HERE

In addition, since the
right hemisphere is dominant in the perception and expression of facial,
somesthetic and auditory emotionality, damage to this half of the brain can
result in a variety of affective and social-emotional abnormalities including
lability, florid manic excitement, pressured speech, bizzare confabulatory responding,
childishness, irritability, euphoria, impulsivity, promiscuity and abnormal
sexual behavior (Bear, 1977, 1983; Bear & Fedio, 1977; Clark & Davison,
1987; M. Cohen & Niska, 1980; Cummings & Mendez, 1984; Erickson, 1945;
Forrest, 1982; Gardner et al., 1983; Gruzelier & Manchanda, 1982; House et
al. 1990; Jamieson & Wells, 1979; Jampala & Abrams, 1983; Joseph,
1986a,1990d; Lishman, 1968; Offen et al. 1976; Rosenbaum & Berry, 1975;
Spencer et al. 1983; Spreen et al., 1965; Starkstein et al. 1987; Stern &
Dancy, 1942).

Individuals so affected
are likely to be viewed as suffering from mania.

For example, M. Cohen
and Niska (1980) report an individual with a subarachnoid hemorrhage and right
temporal hematoma who developed an irritable mood; shortened sleep time; loud,
grandiose, tangential speech; flight of ideas; and lability and who engaged in
the buying of expensive commodities. Similarly, Oppler (1950) documented an
individual with a good premorbid history who began to deteriorate over many
years’ time. Eventually, the patient developed flight of ideas, emotional
elation, increased activity, hypomanic behavior, lability, extreme fearfulness,
distractability, jocularity, and argumentativeness. The patient was also overly
talkative and produced a great deal of tangential-circumstantial ideation with
fears of persecution and delusions. Eventually a tumor was discovered (which
weighed over 74 grams) and removed from the right frontal-parietal area.

One patient, formerly
very reserved, quiet, conservative, and dignified with more than 20 patents to
his name, and who had been married to the same woman for over 25 years, began
patronizing up to 4 different prostitutes a day and continued this activity for
months. He left his job, began thinking up and attempting to act upon
extravagant, grandiose schemes, and camped out at Disneyland and attempted to
convince personnel there to finance his ideas for developing an amusement park
on top of a mountain. At night he frequently had dreams in which either John F.
or Robert Kennedy would appear and offer him advice –and he was a Republican!

Confabulation,
hypersexuality, tagentiality, and manic like behaviors seem to be more
frequently associated with right frontal dysfunction (Joseph, 1986a; 1988a,
1999a), particularly among men. Hence, when the right (or both) frontal lobes
are severely it is not uncommon for those afflicted to behave in an
inappropriate, labile, and disinhibited fashion. Individuals may become
hyperactive, distractable, hypersexual, tangential, and confabulatory and
behave in a childish, impulsive, euphoric manner (e.g. Lishman, 1968). And, it
is just as likely for such individuals to just as suddenly cease their antics
and to become largely unresponsive and seemingly disinterested in their
environment until provoked, sometimes by seemingly inconsequential and trivial
stimuli.

Although men are
probably more likely than women to develop mania with right frontal lesions,
females may be similarly affected, particularly if both frontal lobes and the
orbital areas have been damaged. In one case, for example, a woman of 46 was
admitted to the hospital and observed to be careless about her person and room,
incontinent of urine and feces, to sleep very little and to act in a
hypersexual manner. Her symptoms had developed several months earlier when she
began accusing a neighbor of taking things she had misplaced and on other
occasions stripping in front of him. She began going about in just her
nightdress, informing people she was descended from queens, was very rich, and
that many men wanted to divorce their wives and marry her. During her
hospitalization she was frequently quite loud, disoriented to time and place,
and extremely tangential, jumping from subject to subject. Eventually a
meningioma involving the orbital surface of her frontal lobes was discovered
(Girgis, 1971).

As noted, although
laughing and joking one moment, these same patients can quickly become
apathetic and disinterested and/or irritated, angered, enraged, destructive, or
conversely tearful with slight provocation. Presumably, patients with right
frontal injury are more likely to produce not only manic-like behaviors but
delusional and confabulatory speech due to disinhibition and the flooding of
the speech areas with ideas that are normally filtered out (Joseph 1986a,
1988a). Right frontal injuries are also more likely to mimic orbital injuries
including the loss of regulatory restraint over limbic and thus emotional as
well as motivational functioning. Patients may not only talk too much, but eat
and drink too much, as well as behave in a socially and emotionally
inappropriate manner.

 

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