The best books on Clinical Neuroscience

Thank you for recommending five of the best books on clinical neuroscience. I believe your reading list walks us through the development of the science. First of all, might you talk us through what ‘clinical neuroscience’ is? Does a clinical neuroscientist primarily deal with neurological injuries?

If you cut a good neurologist, a clinical neuroscientist bleeds. Much knowledge of clinical neurology at the bedside was ‘lesion based’; for example, if you are shot through your left inferior frontal lobe, in most cases expressive language will be impaired—what’s called Broca’s aphasia.

Good clinical neuroscience also arises from the laboratory bench. Hubel and Wiesel’s landmark studies of visual cortex changes in cats with one eye sutured shut helped us to prevent blindness in children with strabismus, that is, ‘lazy eye.’ In this way,  basic ‘bench’ vision research came directly to the bedside.

Clinical neuroscience is a two-way street…but it should lead to the patient. The five protagonists—Cajal, Cushing, Kandel, Penfield, and Sacks— in this clinical neuroscience syllabus were MDs, with a few other degrees appended, and although some gave up bedside for the bench, the care of the patient remained a primary goal.

Could you talk us through the rationale for these book recommendations?

I have recommended three exemplary autobiographies, one biography, and one book of case reports of a neurologic disease—which is, for the most part, extinct—to offer an idiosyncratic flyover of 20th-century neuroscience, which is still to be found in the intellectual toolkit of clinicians today.

Got it. The first clinical neuroscience book you’ve chosen is Recollections of My Life, by Santiago Ramon y Cajal and translated by E. Horne Craigie and Juan Cano. It was first published in 1917.

The neuron—the fundamental building block of neuroscience—was validated with the 1906 Nobel Prize… but not without the co-winners Ramon y Cajal and Camillo Golgi volubly airing disagreement from the podium. Cajal re-lived the acrimony in Stockholm in Recollections of My Life, That’s as good a starting point as any (unless you’re partial to the Edwin Smith Surgical Papyrus, dating from circa 1600 BC).

The book details his first attempts at scientific investigation in the late 1880s—when his adaptation of Golgi’s stain of silver bichromate allowed the hitherto impenetrable thicket of neurons, axons, dendrites, and glia to be penetrated by the reazione nera, which “picks out certain nerve cells to the absolute exclusion of others.” To this day we still don’t know how a particular neuron is ‘picked’ to take up the stain but in that heroic age of histology “the gain in the brain was mainly in the stain.”

Very good. For the benefit of our less technical readers: histology is the study of microscopic anatomy.

Mapping of the fine structure of the nervous system had begun, and Cajal’s marvelous histologic drawings are scattered throughout the book.

So, you say the neuron was ‘validated’; had its existence been inferred previously, and these images were our proof? 

In the 1880s the anatomy of the neuron was up for grabs, and in Europe and Scandinavia Wilhelm His, August-Henri Forel, and Fridtjof Nansen (who gave it up for Arctic exploration, eventually winning a Nobel Peace Prize) were in hot pursuit but it was Santiago Ramon y Cajal who must be regarded as the “chief architect of the neuron theory.”  Based on his thousands of drawings of neurons, some with free endings and discontinuities of Golgi-stained axons and dendrites extending from neuron cell bodies, he drew the irresistible conclusion that the neuron was a discrete bounded structure and not part of a continuous network, or syncytium.

History has vindicated Cajal’s neuron doctrine, but it was not until the 1950s that Sanford Palay’s electron microscopy fully revealed the boundary line or ‘synapse’ separating neurons.

Next on your list of recommended clinical neuroscience books, you’ve chosen Harvey Cushing: A Biography by John F. Fulton, published in 1946. It can be a little difficult to get hold of, but I found second-hand copies on both Amazon and Abe Books. This is the Cushing for whom Cushing’s disease is named. Tell us more.

Pre-neuroimaging (and pre-antibiotic) neurosurgery at the close of the 19th century “lay under a shadow” and brain tumor cases were turned over to neurosurgeons “with reluctance and only as a last resort,” as Cushing recalled in 1931. At Johns Hopkins, Cushing’s surgical mentor W.S. Halstead encouraged his resident to go into orthopedics! On his wanderjahr in Berne, Cushing resolved to devote himself “should opportunity arise, to the surgery of this special field”—the nervous system.

There is no more compelling or eloquent evidence of Cushing’s impact on his special field than the timeline of his surgery on 2000 intracranial tumors.  In 1901 after operating three times on a woman with failing vision, headaches, and a pituitary tumor, the patient died. By 1931 Cushing had operated on 360 patients with pituitary tumors, and many had Cushing’s disease with weight gain, cutaneous striae (stretch marks), a ‘moon-like’ face, and a ‘buffalo hump’—that is, fat deposits on the back of the neck. Cushing did not know the hormonal cause—pituitary overproduction of adrenocorticotropic hormone, which was isolated in 1933—but his refined surgical technique with transsphenoidal removal of pituitary tumors through the nasal cavities was a success. His 2000th patient, who also had a pituitary tumor, made a perfect recovery.

I think Fulton, the biographer, had a personal relationship with Cushing.

As a 30-year-old Fulton became a Sterling Professor at Yale and authored the first textbook of neurophysiology. During his training he spent a year on Cushing’s surgical service. Although Cushing was an uncompromising taskmaster, they got along famously, and it has been said that Fulton was the son Cushing never had. After Cushing died in 1939, WWII intervened and Fulton was unable to complete this magisterial biography of his clinical doktorvater until 1946.

“We’re still wrestling with the marvelous complexity of the 86 billion neurons we carry inside our heads”

Cushing as much as anyone embodied the cultural icon of the ‘brain surgeon’ and created the modern specialty of neurosurgery. His pursuits included writing a two-volume Pulitzer Prize-winning biography of his own mentor and pole star, Sir William Osler. At age 46, during the First World War, he sailed to Europe “through the Lusitania wreckage … steamer chairs, oars, boxes, overturned boats – and bodies” to become a US Army surgeon operating “under canvas” on casualties during the battles of Ypres.

Interspersed along the page margins are pen-and-ink sketches by Cushing who could draw craniotomies, landscapes, and people with equal facility.

What a fascinating man. The next clinical neuroscience book you’ve chosen to recommend is No Man Alone by Wilder Penfield, an autobiography published in 1977. Penfield is most famous for his visual map of how the body is represented in the brain’s somatosensory cortex, known as the Penfield Homunculus.

Each cerebral hemisphere’s cortical map of motor & sensory function of the contralateral side of your body is called a ‘homunculus,’ displaying a disproportionally magnified face and hand with a minified shoulder. This distorted hemi-imp was charted by Penfield in 1937 as he stimulated the “eloquent cortex” to find epileptic foci in patients whose seizures persisted despite medications.

The road to the homunculus began after Penfield completed coaching the 1914 Princeton football team and then, as a Rhodes scholar, left the US to begin medical training at Oxford. In wartime Oxford, Penfield was taught by Charles Sherrington—arguably the World’s pre-eminent neurophysiologist, who in 1897 coined the term ‘synapse’. In 1916, while crossing the Channel to volunteer at a Red Cross hospital in France, Penfield’s ship, the S.S. Sussex, was torpedoed, badly shattering his leg. He convalesced at the home of Sir William Osler, the Regius Professor of Medicine at Oxford. At this halfway mark in medical school, Penfield left to finish at Johns Hopkins aspiring to follow in the footsteps of Sherrington and Osler – “the one in science and the other in medical practice and personal life.”

This is the same Osler that acted as Cushing’s mentor?

Neurosurgery in the early 20th century was a small academically inbred discipline, but Osler, an internist, cut across specialty boundaries. During Cushing’s surgical residency at Hopkins from 1896 to 1899, the 47-year-old professor served as a mentor to the resident twenty years his junior. Penfield was an intern on Cushing’s surgical service in 1918-19, but his road diverged from the Cushing school of ever-improving surgical proficiency driven by pressing clinical puzzles such as how to diagnose a cerebral aneurysm before it fatally ruptures.

Penfield resolved to learn about pathological lesions, and neuroanatomy: “Finally someday I would study two other things: the mystery of epilepsy, and how the human brain does what it does.” To accomplish this he sought the great clinical neuroscientists of England and Europe to particularly learn how to clinically examine the nervous system and the brain’s microscopic anatomy. At Queen Square, London’s pre-eminent neurologic hospital, in 1920 Gordon Holmes taught him to localize the cortical focus of epileptic attacks. In 1924 he met with Cajal and Pio del Rio-Hortego in Madrid to master the techniques of staining the cells of the brain. Cajal’s neuron doctrine of 1906 was the background, but if neurons were the building blocks of the central nervous system, Penfield needed to learn about the glia (‘glue’) that supports and holds them together. Sharing work tables, Rio-Hortega taught Penfield how to stain the glial cells: astrocytes, microglia, & oligodendroglia. In 1924 Penfield published confirmation of the existence of the hitherto ‘phantom’ oligodendroglia.

And the book itself is interesting?

No Man Alone recounts Penfield’s steep neuroscientific learning curve before he founded the Montreal Neurologic Institute in 1934 and mapped the cortical homunculus. Along the way, in 1928, he successfully removed the largest brain tumor—a right frontal lobe oligodendroglioma – he had ever encountered. And the patient was his sister!

Penfield completed the final draft just three weeks before his death. Unlike many neuroscientists, he was a dualist, and No Man Alone narrates what he calls his “pilgrim’s progress” of “exploration of brain and mind.” Mysticism aside, Penfield was a maverick with an approach to neurosurgery that was very different from Cushing’s. Penfield began training when the electrical nature of epileptic discharges was unknown. The first electroencephalogram, or EEG—the gold standard of epilepsy diagnosis—would not be performed until 1924, but by the 1930s Penfield was using the EEG and bipolar electrodes to map the brain.

It’s quite mindbending to think of the early days of clinical neuroscience, when so little was known and understood. When a patient presents with baffling symptoms, where would you even start?

I remain fascinated by his approach to the terra incognita of the brain forged by his caution (“first do no harm”) and counterweighted by his “desperate measures” such as cortical resections. These concepts intersected when Penfield performed a unilateral temporal lobectomy to control intractable complex partial seizures.

In 1951 and 1952, two such patients unexpectedly sustained severe loss of their ability to retain recent memories. Penfield later found that each patient had prior unsuspected damage to the ‘normal’ opposite temporal lobe, setting the stage for our modern conception of the critical role of the bilateral temporal lobes/hippocampi for short-term/recent memory retention. Had William Beecher Scoville known this—or employed Penfield’s caution—on September 1, 1953, when he attempted to cure patient HM’s intractable epilepsy by bilateral removal of 8 cm. of hippocampus posterior to the tips of the temporal lobes, HM would not have been consigned to the “eternal present”—and the subject of the most detailed neuropsychological and neuroanatomical studies of any human to date.

That’s a case both shocking and fascinating in equal measure; Scoville’s grandson, Luke Dittrich wrote a fascinating book about patient HM, published in 2016. Now, the next book on your clinical neuroscience book list is In Search of Memory by the Nobel Prize-winner Eric Kandel.

The locus of memory was, and is, a major problem for clinical neuroscience. By 1958 Penfield conceded his mistake of equating the ‘memory cortex’ with certain parts of the temporal cortex which he came to regard as the ‘interpretative cortex.’ And the search for memory is the overarching theme of Eric Kandel’s memoir.

In stark contrast to playing baseball at Yale (Cushing) and football at Princeton (Penfield), in the aftermath of Kristallnacht in 1939 10-year-old Kandel and his family fled their home in Vienna, the nexus of art & science which vanished in the conflagration of WWII. Kandel did later attend Harvard and, perhaps with a view to exorcise the demons of his childhood home, studied European intellectual history with an interest in how “fine” German minds succumbed to National Socialism.

“We’re still a long way from finding the neuroscience Holy Grail that unlocks the ‘hard problem’ of consciousness”

Upon meeting two members of Freud’s circle, his interests underwent a sea-change and he resolved to attend medical school and become a psychoanalyst…but with a radically different approach to the Freudian icons of ego, superego, and id. On elective in the neurophysiology laboratory of Harry Grundfest, Kandel put forth his wild surmises as to “where in the elaborate folds of the human brain … [Freud’s] psychic agencies might live.” Grundfest “told me, to understand the mind we needed to look at the brain one cell at a time.” Alea jacta est.

Kandel set out to prove that mental experiences change the structure of the brain. He chose to study the 20,000 neurons comprising the nervous system of the foot-long marine snail Aplysia californica on an informed (and inspired) hunch without a preliminary dissection of the creature. Its large synaptic potentials eventually enabled him to work out for the first time the precise wiring diagram of a behavior, and that “by producing profound structural changes, learning can make inactive synapses active or active synapses inactive.” In keeping with the synaptic leitmotif running through 20th-century neuroscience, Kandel established that short-term memory transiently strengthens pre-existing synaptic connections and long-term memory alters gene expression & protein synthesis and grows new and stronger synapses.

After graduating from medical school, Kandel completed a medical internship, pursued neurophysiology for three years at the National Institutes for Health, and then returned to Harvard for a residency in psychiatry. Subsequently Kandel, in a state of psychoanalytic apostasy, struggled mightily to persuade his psychoanalytic colleagues of the linkage of mind and brain. After outlining his plans of studying learning in Aplysia a distinguished psychiatrist muttered, “It sounds to me as if your psychoanalysis was not fully successful; you seem never really to have quite resolved your transference.” These carping Freudian ex cathedra criticisms were the regrettable norm for a specialty that “treated the brain as a black box” and thankfully did not deter Kandel. In fairness to his psychoanalytic colleagues, the idea of studying the human mind via invertebrates was pretty radical at that time.

Psychoanalytic training may have left its mark, but Kandel’s studies of the simplest of neural circuits underscored his belief that “given the importance of unconscious psychic processes, it is reassuring to think that biology can now teach us a good bit about them.”

Yes, I see how that could be a leap. And your final book recommendation is the brilliant Awakenings by Oliver Sacks (1973), one of my favorite books of all time. Why do you think this book reached such a wide audience?

The turning point for Sacks as a writer was to read A.R. Luria’s (the Russian ur-neuropsychologist) Mind of a Mnemonist in 1968. Those 160 pages served as an exemplar not only for Awakenings but for everything he was to write… by emulating Luria’s skill at “combining the classical and the romantic, science and storytelling.” His publishers Faber & Faber were not interested but with the acclaim of W.H. Auden, Duckworth published the book in 1973. An accessible non-fiction account of his sleeping-sickness/post-encephalitic Parkinson’s patients at the fictional ‘Mount Carmel’ hospital in imaginary ‘Bexley-on-Hudson’, with an eye for clinical detail lost since the great 19th-century neurological case narratives of Hughlings Jackson, Awakenings sold 5 million copies worldwide. Popular acclaim can be the kiss of death for scientific gravitas—the so-called ‘Sagan effect’—and Sacks was pigeonholed as a popular science writer by the academic neurology establishment, never receiving his due as an accomplished clinical neuroscientist.

Sacks, a neurologist without university support for most of his career, was arguably the foremost neurologic belle-lettrist of his generation. Poignantly and meticulously he set down the case histories of 20 of his patients at Beth Abraham Hospital in the North Bronx. These patients had post-encephalitic Parkinsonism brought on by von Economo’s encephalitis which raged worldwide in 1916 and 1917 and “took or ravaged the lives of nearly five million people before it disappeared, as mysteriously and suddenly as it had arrived, in 1929.”

How weird and frightening.

Sacks, writing with unmatched descriptive and almost novelistic power, portrayed his wards “as insubstantial as ghosts, and as passive as zombies”; von Economo compared them to “extinct volcanoes.” Through Sacks’ widened eyes we bear witness to the responses of these patients to “a remarkable new ‘awakening drug’ L-dopa (L-3,4-dihydroxyphenalanine)—a metabolic precursor of the neurotransmitter dopamine, which is severely depleted by the degeneration of dopaminergic neurons in the substantia nigra of Parkinson’s disease patients.

The first patient Sacks introduces is Frances D., a 65-year-old woman who had contracted encephalitis lethargica fifty years earlier. For the most part, she recovered and had a successful career as a legal secretary until her mid-forties when she developed “a more sinister set of symptoms” – alternating between freezing and hurrying of her movements and speech – typical of the dopamine depletion that is the signature of Parkinsonism. Increasingly incapacitated, she was admitted for chronic care to ‘Mount Carmel’ (Beth Abraham) in 1969, and over the course of 33 pages Sacks describes the therapeutic journey of his patient of “superior intelligence,” doubled up posture and “humorous eyes” in an expressionless face, beginning with initiation of 0.5 gm of L-dopa on 25 June, 1969.

It is a very rough ride for patient and doctor alike written with a jarring admixture of dispassionate clinical detail and Miss D.’s “astonishment, rage, and terror” at the vicissitudes of her clinical course.

In 1973 Awakenings was without precedent and Sacks’ voice helped to confirm my nascent interest in neurology as a third-year medical student. Sacks treated over 200 patients at Mount Carmel and, in the pages after Frances D., there are 19 more case reports “of our most complex sufferings and disorders of being.”

As an academic outsider, Sacks’ formal scientific communications (“of the lives and responses of these patients which have no real precedent in the history of medicine”) were given short shrift by medical journals. He chose instead the larger canvas of this book of case histories of patients he treated for almost seven years. They transcended pathography and, he wrote, “composed a strange sort of Odyssey, through the deepest and darkest oceans of being.”

One has the sense with Sacks’ writing—and other writers in this field—of the human brain being true strangelands. Neuroscience is not a field that demystifies, exactly—but makes things stranger still. Would you agree? Is that what drew you to the field?

The sense of wonder about the human neurologic condition is all-too-often dulled by the daily workflow of diagnosis and treatment. Oliver Sacks’ oeuvre is a powerful restorative for the fascination that starts us out in the practice of the field of applied human biology called, simply, ‘medicine.’ Or as in Osler’s epigram used by Sacks to open The Man Who Mistook His Wife for a Hat: “To talk of diseases is a sort of Arabian Nights entertainment.”

Clinical neuroscience is a relatively young science. Although we’ve come a long way since the jousts of Cajal and Golgi in 1906, we’re still wrestling with the marvelous complexity of the 86 billion neurons we carry inside our heads. Looking backward from the dawn of neuroscience recognizable to current practitioners, neurons and glia begat synapses and neurotransmitters like dopamine, which begat action potentials. Then local circuits led to distributed networks subserving language, vision, emotion, memory, and anon. “And anon” is pointed at the neural correlates of consciousness—reverberating thalamocortical circuits? Crick’s claustrum? everything (panpsychism)? We’re still a long way from finding the neuroscience Holy Grail that unlocks David Chalmers’ ‘hard problem’ of consciousness!

As an English major going to medical school in the 1970s, psychiatry exerted a strong humanistic attraction for me. Neurology had been approaching many of the questions posed by psychiatry but neurology advanced as the tools of physiology were refined and the ‘wiring diagrams’ of neuroanatomy jumped from the pages of anatomy atlases to the images generated by CT and MRI neuroimaging. Some of my teachers practiced “neuropsychiatry”—an amalgam rarely encountered today—but the two fields remain inextricably linked. Every U.S. board-certified neurologist is granted his or her bona fides by the American Board of Psychiatry and Neurology.

The adventure of exploring the science of the brain and treating its disorders was irresistible and persuasively abetted by Cajal, Cushing, Penfield, Kandel, and Sacks. I keep an open mind to the dualism of Penfield but I fervently hope for a resolution of the explanatory gap between mind and brain. We shall see.