Richardson, RT, ed. (1991) Activation to Acquisition: Functional Aspects of the Basal Forebrain Choliniergic System. Birkhauser: Basel. (published in 1991 Behav Pharmacol 2:530-531)

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Sacks O (1985) The Man Who Mistook His Wife for a Hat and Other Clinical Tales.  Harper & Row: New York

This book has been on my shelf for many years awaiting its turn on my to-read pile.  I decided finally to read it because I will be teaching an undergraduate course in brain and behaviour in the coming year and thought it might provide some helpful anecdotes.  It did.

One thing that struck me was the almost total absence of any discussion of mechanism.  Although a number of fascinating cases are presented in a readable and enjoyable manner, there is almost no reference to the brain structures that may be involved and neurotransmitters are almost nowhere to be found.  However, Sacks wrote the first edition of this book in 1970 at a time when much less was known in neurology and neuroscience had not yet emerged as an independent discipline.  Also, Sacks appeared to be targeting a lay readership with limited knowledge of the central nervous system.

Sacks provides many lively descriptions of patients.  The title character, the man who mistook his wife for a hat, had prosopagnosia, a form of visual agnosia characterized by an inability to recognize faces. No mention of the fusiform gyrus, the region likely damaged in this patient.  Of a patient with anterograde amnesia, Sacks explains that it was not that he failed to register memories, but that they were effaced in minutes.  He explains that emotional reactions continue to take place even though memories are lost, anticipating the recognition of declarative and non-declarative memory types that are differentially affected by brain damage to a specific area.

I found the discussion of an aphasic patient interesting as Sacks pointed out how she had an enhanced sense of tone.  The rhythm of speech is termed, ‘prosody’ and may be mediated on the right side of the brain in a regions analogous to the left-side regions for speech reception and production that are damaged in aphasics.  Damage to one side might lead to enhanced function of the other side.  Sacks’ observations are consistent with this dissociation.

Sacks provides a wonderful description of the experience of a patient who is taking the antipsychotic dopamine receptor blocking drug haloperidol (Haldol) to treat Tourette’s.  Under the influence of the drug, “He is slow and deliberate in his movements and judgments, with none of the impatience, the impetuosity, he showed before Haldol, but equally, none of the wild improvisations and inspirations.  Even his dreams are different in quality: ‘straight wishfulfillment,’ he says, ‘with none of the elaborations, the extravaganzas, of Tourette’s’.  He is less sharp, less quick in repartee, no longer bubbling with witty tics or ticcy wit.  He no longer enjoys or excels at ping-pong or other games; he no longer feels ‘that urgent killer instinct, the instinct to win, to beat the other man’; he is less competitive, then, and also less playful; and he has lost the impulse, or the knack, of sudden ‘frivolous’ moves which take everyone by surprise.  He has lost his obscenities, his coarse chutzpah, his spunk.  He has come to feel, increasingly, that something is missing.” (page 100).  Haloperidol blocks dopamine receptors in the brain thereby reducing dopaminergic neurotransmission.  Dopaminergic neurotransmission decreases naturally with age.  I couldn’t help think that this description of the effects of haloperidol paralleled the experiences of aging.  (July 24, 2010)

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Sacks O. (1990) Awakenings. HarperCollins: New York

Until L-DOPA became available for treatment in the late 1960s, people with advanced Parkinson’s disease or post-encephalic parkinsonism were generally doomed to an invalided life in the back wards of hospitals, many times with little or no ability to look after themselves.  The worldwide epidemic of the sleeping sickness, Encephalitis lethargica began near the end of the First World War and by the time it disappeared in 1927 had ravished the lives of over five million people.  Some recovered only to be stricken later in life with post-encephalic parkinsonism.  Some of these post-encephalic patients were hospitalized at ages as young as 25 years and, by the time they eventually were treated by Dr. Sacks with L-DOPA, had been in a relatively non-responsive state for as many as 40 years.  In what has now become a well-known phenomenon as a result of this book, and in part as a result of movies and documentaries that followed original publication of this book in 1973, when given L-DOPA these patients woke up; they began again to move and speak and their long-lost personalities re-emerged.  This was truly a marvel and Awakenings is the story of the lives of these patients, before during and after L-DOPA.  It is a fascinating story well told by Sacks.

Parkinsonism is caused by a loss of the brain’s dopaminergic neurons, cells that are located in the ventral midbrain and that project forward to a region termed the striatum because of its stripy appearance in dissected brain tissue.  Dopaminergic neurons are so-named because they produce and release the chemical neurotransmitter dopamine.  Dopamine acts as a sort of clutch in the brain, engaging cortical circuits that process information about the world with output circuits that function to produce motor acts like walking, reaching, grasping and smiling.  As a result of the action of dopamine, we are able to convert our will into action.  The decision to walk to the store is all anyone needs to then walk to the store assuming that their body is not disabled by damage to muscles or bones, for example.  For the Parkinson’s patient, suffering from the loss of brain dopamine, the will to act does not necessarily lead to the action.  It is important to understand that Parkinson’s patients are not unable to act per se.  Intense and/or frightening stimuli, for example a fire alarm, can cause Parkinson’s patients to get up and run out of a building, only then to collapse again into their unresponsiveness.  It is really that without dopamine, the will to act and the action itself are no longer linked.

One of the questions that I have often wondered about was what mental experience would be like without dopamine.  Would the unmedicated parkinsonian individual have a rich mental life filled with the recollections, plans, dreams and fears normally experienced but be unable to convert any intention into action?  I looked for the answer to this question in Awakenings.  (This edition of Awakenings included all the copious footnotes that were omitted from previous editions and I found some of the material I was looking for in the footnotes.)  When discussing the meaning of “akinesia”, Sacks speaks of a, “…retardation or resistance which impedes movement, speech and even thought, and may arrest it completely.  Patients so affected may find that as soon as they ‘will’ or intend or attempt a movement, a ‘counter-will’ or ‘resistance’ rises up to meet them” (p. 7, Sacks’ italics).  On the one hand, the definition makes it sound like even thought may be arrested.  On the other, it sounds like movements might be willed but then arrested by a counter-will.  So is there will?

Parkinsonism is gravity, L-DOPA is levity” (p. 8, footnote 11).  “(T)here is…in many akinetic patients, a corresponding ‘stickiness’ of mind and bradyphrenia, the thought stream as slow and sluggish as the motor stream.  The thought stream, the stream of consciousness, speeds up in these patients with L-DOPA…” (pp. 8-9, footnote 12).  These comments strongly suggest that the motor slowing experienced in parkinsonism has associated with it a mental slowing.  This suggests that parkinsonian individuals do not have the rich mental life that is experienced by people with intact dopaminergic neurotransmission.

It appears that as decreases in dopamine levels progress with the disease, motor slowing and mental slowing proceed apace.  The will is not lost immediately but gradually weakens as thoughts slow.  Thus, Sacks describes Charcot’s observations of patients who would sit for hours not only motionless but with no impulse to move, apparently lacking will to engage in any activity.  Before L-DOPA, patients apparently registered what was happening around them but with a lack of attention and a profound indifference.  All aspects of being and behaviour, including thoughts, appetites, and feelings, no less than movements, were brought to a standstill.  One patient, after receiving L-DOPA reported, “It is so long since I had any feelings” (p. 101-102).  This suggests that unmedicated parkinsonian patients do not think or feel or, perhaps, that the thought that does occur takes place very slowly.  Apparently, without dopamine there is not only a loss of movement, but a loss of attention, thought and feeling.

Although an unmedicated parkinsonian patient apparently does not attend, think, feel or move, the individual does perceive.  One patient, after receiving L-DOPA, described her experience while in a parkinsonian state:  “I ceased to have any moods… I ceased to care about anything.  Nothing moved me – not even the death of my parents.  I forgot what it felt like to be happy or unhappy.  Was it good or bad?  It was neither.  It was nothing” (p. 71).  Another patient who was unresponsive for 43 years, upon awakening with L-DOPA reported, “I can give you the date of Pearl Harbor… I can give you the date of Kennedy’s assassination.  I’ve registered it all – but none of it seems real… I’ve been a spectator for the past forty-three years” (p. 83, footnote 58).  Yet another patient described her experience as being aware of what was happening around her and of what the date was but that she herself had, “no feeling of happening” (p. 167, Sacks’ italics), only the feeling that time had stopped.  These comments suggest that there was awareness and a sense of self but, as already described, no feeling.  The Parkinson’s patient does perceive events but she does not have any feeling about them.  It would appear that dopamine is not necessary for self-awareness, the sense of “I”.

Most patients who responded to L-DOPA eventually became sensitized to it so that they frequently entered states of enhanced dopaminergic neurotransmission.  This was often associated with hyperkinesia, the opposite of the bradykinesia seen before L-DOPA was introduced.  There are often comments about mental experiences while in this state that are opposite and complementary to those described above for decreased dopamine.  For example, one patient in a state of enhanced dopaminergic neurotransmission reported being forced to think things, the opposite of the absence of thought before L-DOPA.  Sack’s described the art, a drawing of a tree, of one patient before L-DOPA, “… a small, meager thing, stunted, impoverished, a bare winter tree with no foliage at all”, on L-DOPA, “…the tree acquires vigor, life, imagination – and foliage” and during L-DOPA-induced dopaminergic hyperfunctioning, “…the tree may acquire a fantastic ornateness and exuberance, exploding with a florescence of new branches and foliage with little arabesques, curlicues, and whatnots, until finally its original form is completely lost beneath this enormous, this baroque, elaboration” (p. 155, footnote 80).  One patient described her experience on L-DOPA as, “So tingly, like my blood is champagne.  I am bubbling and bubbling and bubbling inside” (p. 156).  Increased dopaminergic neurotransmission led to a flood of thoughts and actions and strong feelings.

It seems that even when dopaminergic neurotransmission is low and producing a parkinsonian state, signals in cortical circuits can “break through” to produce motor acts.  For example, Sacks described the apparent lifting of Parkinson’s disease by interesting or activating situations; I mentioned the fire alarm example above.  Immobile patients can walk if another person accompanies them.  One patient described it this way:  “When you walk with me, I feel in myself your power of walking.  I partake of the power and freedom you have.  I share your walking powers, your perceptions, your feelings, your existence” (p. 282).  Parkinson’s people can similarly be activated by music.  These observations suggest that some stimuli may be able to activate a hypofunctioning dopamine system to the level needed for motor control to be engaged.  In recent years it has been found that social cooperation can activate regions of the brain that contain dopaminergic cell bodies or that receive dopaminergic input.  These findings from functional magnetic resonance imaging (fMRI) studies provide independent support for the observation that some stimuli can produce motor activation in parkinsonian patients.

Two final observations caught my attention.  One was that a patient who received L-DOPA declared, “I feel like a man in love” (p. 209).  Recent fMRI studies have shown that being in the early stages of romantic love leads to evidence of increased dopaminergic activity.  Perhaps it follows that L-DOPA-enhanced dopaminergic activity leads to feeling like being in love.  The other was the idea of latent Parkinson’s disease.  The idea was that there may be people with low dopamine levels but not levels low enough to cause symptoms.  However, when these people experience life events that may lead to lowering of dopaminergic neurotransmission, e.g., depression, the symptoms of Parkinson’s disease may suddenly emerge (see p. 238, footnote 115).

The stories of post-encephalic patients with parkinsonism who were treated with L-DOPA provide a unique opportunity to learn about the experiences of people who live in a state of low dopamine.  Now that L-DOPA and related drugs are available it is rare to find people in this state.  Thus, Awakenings is a valuable resource for students of dopamine and behaviour in particular and neurotransmitters and behaviour in general.  Dr. Sacks has provided a treasure trove of clinical observations.  (Sept. 7, 2010).

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Striedter, GF (2005) Principles of Brain Evolution. Sinauer Associates Inc.:Sunderland MA, USA.

Striedter suggested that early evolutionists like TH Huxley (1825-1895) who knew poverty and struggled to advance his social position may have seen evolution as advancing in a somewhat similar linear manner.  C Darwin (1809-1882), by contrast, was wealthy from birth and was more inclined to see evolution as branched; he viewed speciation by natural selection as producing family trees.  In spite of this distinction, the linear notions of Huxley and others and the scala naturae that they suggest influenced thinking about species well into the XX century and comparative anatomists are quick to point out this error in thinking.

We have come a long way from these early notions.  Neurocladistics has clarified the homology concept (shared derived characters) by presenting a clear methodology for reconstructing the phylogenic history of individual characters.  Once cladists find enough homologues they can build robust classifications thus advancing comparative neurobiology.  It is never easy, though, and even highly conserved systems like those that utilize the neurotransmitters norepinephrine, serotonin or dopamine show variations among vertebrate groups, e.g., teleosts and mammals, that are still difficult to interpret.

Relative brain size (brain:body ratio expressed in log-log plots) is a useful metric for comparing groups.  It turns out that the mammals and birds have the largest brain sizes compared to total body size.  Ratios are lower for reptiles and amphibians with, perhaps surprisingly, cartilaginous fishes in between.  Some researchers and theorists have wondered about the pressures that would lead to larger relative brain size.  One possibility is that larger brains are needed for living in social groups but the correlation between social group size and relative brain size in 24 primate species is poor.  A significant correlation was found, however, between grooming clique size and relative brain size. 

Striedter talks about the “guts-for-brains” hypothesis recently discussed by A Gibbons (2007, Science 316, 1560); as we moved to a calorically richer meat diet, we needed to invest less energy in gastrointestinal function and could use that energy to fuel a larger brain.  Predigesting meat by cooking it may have helped.  Striedter suggests the chicken-and-egg alternative that as brain size increased, the dietary shift to meat became possible.  As is so often the case, it is probably some of both.

How our neocortex got to be so large is an interesting question.  It appears that here there is evidence for the emergence of new areas, possibly resulting from an older area developing during ontogenesis into two areas instead of one.  The evidence suggests that brain complexity increased independently in different lineages.  Mammals and teleosts share complex diencephalons but in mammals the dorsal thalamus segregated into many nuclei while in teleosts the posterior tuberculum became more complex.  “…complex brains evolved repeatedly among the vertebrates but the details of the complexity tend to vary between clades” (p. 214).

The evolution of neuronal connectivity provides many insights into the workings of genetics and the targets of evolutionary change.  Developing neurons compete for a trophic factor from muscle, a case of epigenetic population matching.  This eliminates the need for genes to specify the specific wiring of muscles.  Epigenetic cascades take place, for example, in the visual system where increased retinogeniculate projections lead to increased geniculocortical projections.

I particularly enjoyed the discussion of the corticospinal tract.  I have known for many years that it is most developed in primates and much less developed or almost nonexistent in other mammals.  Only placentals with a well-developed motor cortex have a well-developed corticospinal tract.  “…with increasing neocortex size, corticospinal axons penetrate deeper into the ventral horn... and further down the spinal cord” (p. 238).  Most people who think about the basal ganglia think in terms of cortico-striato-thalamo-cortical loops that ultimately influence motor cortical output represented by the corticobulbar and corticospinal projection systems.  However, these same loops can be found in species that lack extensive corticospinal tracts; in these cases, cortical output to the striatum must be able to reach brainstem and spinal motor nuclei via another route.  That route would be via caudally coursing basal gangliar output that does not loop back through the thalamus.  The anatomy of these caudally projecting noncortical (extrapyramidal) motor influences remains to be fully worked out.

The comparison of mammalian and avian brains has always been a challenge for comparative neuroanatomists because it has proven difficult to identify apparent homologous structures.  In recent years the realization that the dorsal ventricular ridge of birds has undergone extensive elaboration has helped to sort this out.  This region is even layered like mammalian cortex.  The Wulst is the bird’s most likely homologue to the mammalian neocortex. 

Lots to learn in this book. (March 27, 2008)

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Vanderwolf, CH. (2003) An Odyssey Through the Brain, Behavior and the Mind. Kluver Academic Publishers: Boston MA.

Vanderwolf spent the last 40 years studying the behavior and electrophysiological brain activity of rats and related species. He is a brilliant behavioral scientist who eschews outmoded and ineffective mentalistic concepts in psychology, advocating a brain-and-behavior approach. This book is autobiographical and throughout one meets various figures from Canadian and international psychology who are well known in the field. There is periodic reflection about his own ideas and the direction that his research took, musings about his own ridiculous ideas and the blind alleys that they took him down. There is too a large contribution to the field. Vanderwolf identified a systematic relationship between hippocampal and cortical electroencephalographic (EEG) activity and various types of behavior. He meticulously sought and found the neurotransmitter systems that mediate this EEG and in so doing debunked earlier twentieth century ideas about the reticular activating system. He tells a story about this discovery and his communication of it at a scientific meeting that was not very warmly accepted. It was that old familiar feeling that any scientist knows when he or she comes up with an idea that goes against the current trends.

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