Neuropsychology Peers Deeply Into Schizophrenia's Disabling Chaos

Consider your thinking-life (your mind) as a card game. The game progresses as more and more cards are dealt to players, and those players are tasked with arranging their cards in different ways. These arrangements are how players earn points and, possibly, win the game. As a player, you're always taking these new cards and figuring how to make them work with the other cards; the whole thinking process is one of continuous building, a fundamentally algorithmic sorting/discarding scheme designed to maximize relationships between concepts while being subject to regular infusions of randomness.

Brains are good at this.

The best way I can describe schizophrenia is if a player in the aforementioned game were subject to new, highly disadvantageous rules. As the dealer goes around and around during a given hand/game, and all of the other players build, arrange, and sort their sets of cards into better and more elaborate sequences, you're forced to return all of your cards every turn. Instead of building and refining order from the randomness of a shuffled deck, your cards are always fresh off that deck, with its same degree of disorder. The end of the game/hand comes around and everyone lays out their cards: two pair, royal flush, straight. You, on the other hand, have a disordered jumble—and that's your whole reality.

A paper out this weekend in the journal Biological Psychiatry describes the deficit in somewhat more tactile terms: a failure to transmit goal-directed messages through the physical brain. The cards are there, but the player is unable to see the potential hands. The study for the first time puts this in neurological terms—the structures of the brain that govern desire and emotion don't properly communicate goal-oriented messages to the cortical regions in charge of decision making. The result is a kind of stagnation or "twilight," an inability to accomplish things and generally move forward in life. It's all just piles of increasing disorder, an always-growing entropy between here and the future.

The effect can look—and feel—a bit like the color or substance has drained from the world and the most persistent "negative" symptoms of schizophrenia include a lack of motivation, disinterest in relationships, and a general lack of pleasure. Newer atypical antipsychotics are amazing at knocking out the "positive" symptoms—including delusions, hallucinations, and paranoia—but not so much the grey life-stall that schizophrenia often brings. As such, a huge component of the disease remains almost entirely untreatable and schizophrenia persists as one of the most disabling conditions worldwide.

The current study consisted of two experiments. In the first, participants were tested using different snack foods (a pretty good probe for testing rewards/pleasure in the brain). The schizophrenic set of participants were found to experience the same basic enjoyment as the healthy set, and when the value of that snack was reduced, both sets subsequently chose an alternative. All of this was more or less expected, but what the researchers found was that when the schizophrenic set was asked to choose between a new preferred snack and the devalued snack, they had difficulty in making that decision.

The second part used fMRI scans to monitor brain activity during new tasks that involved learning activities and, again, snack foods. What the team found was that in schizophrenic patients, the part of the brain (the caudate) in charge of actions and choice was severely limited, while activity in the actual decision-making center was about normal.

"Pathology in the caudate and associated brain regions may prevent schizophrenic subjects from properly evaluating their desires then transmitting that information to guide their behavior," said Richard Morris, the paper's lead author, in a statement. "This means that desires and goals are intact in people with schizophrenia, however they have difficulty choosing the right course of action to achieve those goals. This failure to integrate desire with action means people with schizophrenia are stuck in limbo, wanting a normal life but unable to take the necessary steps to achieve it."

It should be cautioned that these findings are still rather early in our understanding of the disease's physiology. "Because this is such a recent discovery, there are currently no treatments which target this region," Morris told me. "Most treatments target [the] ventral striatum, a subcortical region below the caudate. One reason our study is important in this context is because it is the first to establish the real-life consequences of caudate pathology for patients, i.e., a general inability to pursue and achieve goals like employment, education, and social relationships."

"And our findings highlight how critical it is that new treatments are tested for efficacy for this problem," Morris said. "The good news is Professor Bernard Balleine has already developed the animal models to test new compounds, and this model has also been well-validated in other labs around the world."

For now, patients are left with a shuffled deck, perhaps with an amazing hand or a potentially amazing hand (potentially amazing life), but connecting the desire for that amazing hand with the outcome and deciding how to actually arrange the cards remains out of bounds. It's a far deeper thing than realizing life goals, of course; the negative symptoms of schizophrenia mean not just sorting out an amazing or even regular life, they often mean not being able to sort out how to have an amazing lunch or have a functional conversation. They mean not being able to play the game itself—and the game is everything.