Unwanted thoughts can haunt our daily lives – negative memories, worries, or simply off-task thinking. But most healthy adults can control such thoughts. For individuals suffering from neuropsychiatric disorders such as schizophrenia, depression, or post-traumatic stress disorder (PTSD), however, the ability to control such thoughts is greatly hampered. In a new study, neuroscientists have identified a key contributor to this phenomenon: a dearth of a neurotransmitter called GABA in the brain’s hippocampus.
“We focused first on healthy individuals without depression or anxiety to determine whether hippocampal GABA concentrations predicted their ability to control intrusive thoughts,” says Michael Anderson of the University of Cambridge, senior author on the paper published in Nature Communications last month. “We wanted to provide a ‘proof of concept’ that such a relationship exists.”
In the study, led by Taylor Schmitz, the researchers asked participants to perform two separate cognitive tasks that challenged their ability to stop either thoughts or actions, while scanning their brain activity with fMRI. In the thought suppression task, participants learned pairs of reminders and memory items until they formed a strong association between the two. When presented with the reminders, one at a time, researchers asked them to either think of the associated thought or to suppress any thoughts about it. The researchers also measured the participants’ concentrations of GABA in different brain areas using magnetic resonance spectroscopy.
“Strikingly, we found that the more GABA our participants had in the hippocampus, the better they were at controlling their thoughts,” Anderson says. “Our findings indicate that hippocampal GABA enables the prefrontal cortex to disrupt hippocampal retrieval processes. In contrast, the ability to stop an action, instead of a thought, did not rely on hippocampal GABA.”
CNS spoke more about the study with lead author Schmitz – covering everything from the importance of translational, cross-species research to how the research could affect understanding of psychiatric disorders.
CNS: Why is this research area important to you?
Schmitz: Unfortunately, research findings in human and non-human animal models often remain isolated from one another. This is a big problem. Our progress in advancing potential treatments for psychiatric disorders is greatly hampered by “data isolation.” We must understand these disorders from the ground up — from cell communication to cognitive symptoms — in order to devise the most effective treatment strategies.
I was fortunate to do my Ph.D. in a lab where great emphasis was placed on cross-species translational neuroscience work, which forced me to think about neuronal mechanisms of attention and cognitive control at multiple scales—from cell populations to cognitive processes. I’ve been wanting to do a study like this since my Ph.D. and got the opportunity in Cambridge with Michael Anderson.
CNS: How is this work cross-species and translational?
Schmitz: In this research project, we focused on a high-level cognitive process relevant to symptoms, the ability to stop unwanted thoughts. We then related this process not only to interactions between brain systems — the prefrontal cortex and hippocampus — but also to inhibitory neurotransmission (GABA) in the hippocampus, providing a link to preclinical animal models focusing on GABAergic interneurons in the hippocampus. This type of project thus integrates data from diverse methods and subdisciplines in an exciting way, translating the implications of preclinical work to processes related to human concerns.
CNS: How do you like to explain GABA and GABAergic inhibition?
Schmitz: GABA is an inhibitory neurotransmitter. Neurons can be broadly divided into excitatory and inhibitory varieties. Excitatory cells send signals to connected neurons that excite them, increasing their activity, while inhibitory ones like GABA do the reverse. The tendency for inhibitory interneurons to suppress activity in connected cells is critical to many functions in the brain, including, for example, the need to tune, or even to terminate, processing in a population of cells.
CNS: What have we known previously about intrusive memories and psychiatric disorders?
Schmitz: Most of us take for granted our ability to control our thoughts, but if you think about it, this basic ability is fundamental to our wellbeing. This becomes very clear when this capacity breaks down, as it does in many psychiatric disorders, where it causes some of the most debilitating symptoms: intrusive memories, images, hallucinations, ruminations, and pathological worries. Most clinically oriented cognitive neuroscientists are aware of the critical role that the prefrontal cortex plays in exercising this type of control over unwanted thoughts, and how prefrontal deficits may contribute to clinical disorders. Few researchers interested in perseverative thoughts, however, have focused on the potential role that hippocampal hyperactivity might play in generating these problematic symptoms, or the role of hippocampal GABA deficits in generating this pathological state in multiple disorders, including PTSD, schizophrenia, depression, and anxiety.
CNS: What was the new insight you were seeking with this study?
Schmitz: The major goal of the study was to understand the fundamental neural mechanisms that enable people to suppress intrusive thoughts when they need to, and then to forget them. Of particular interest was to determine whether hippocampal GABA plays a role in achieving this critical mental function.
We were inspired to look at this question because a growing body of research in psychiatry has identified elevated BOLD signal in the hippocampus, especially during rest, as a common feature of many disorders associated with intrusive symptomatology, with the degree of “hippocampal hyperactivity” predicting intrusive symptoms. Critically, work in cross-species translational psychiatry — using animal models to study psychiatric conditions such as schizophrenia and anxiety — suggest that compromised GABAergic interneurons contribute to this condition, “disinhibiting” the hippocampus.
We hypothesized that when people suppress intrusive thoughts, the prefrontal cortex may drive GABAergic processes in the hippocampus to restrain or inhibit retrieval activity, diminishing the unwanted thought. This may be why lacking GABA in the hippocampus is associated not only with hyperactivity in that structure, but also intrusive symptoms. Such symptoms in clinical populations may represent the extreme end of a continuum of individual variation in hippocampal GABAergic function.
If our neurotransmitters are severely altered, for example by disease, this will influence our cognitive capacities and our behaviors, which define who we are.
CNS: What were your most excited to find?
Schmitz: The most surprising observation for me was how selectively the hippocampus predicted both brain activity and behavior during thought suppression. In our study, we looked at GABA concentrations in multiple brain areas, including the prefrontal cortex. We also contrasted thought suppression with another type of inhibitory control: suppression of motor responses. Strikingly, only GABA in the hippocampus mattered to successful thought suppression, and not GABA in other brain regions that we examined; and hippocampal GABA only mattered to thought suppression and not motor action inhibition.
CNS: What do you most want people to understand about this work, especially as it relates to patients?
Schmitz: This work suggests that the ability to control unwanted thoughts — whether they are worries, ruminations, images, or memories — is not simply determined by the integrity of cognitive control processes mediated by the prefrontal cortex, as many researchers have previously thought. Rather, the success of the prefrontal cortex in shutting down clinically bothersome thoughts may be significantly determined by the integrity of GABAergic inhibition processes within the hippocampus, which may be separately affected by disease and disorder.
This discovery should expand the attention of clinically oriented researchers to the role of the hippocampus, and especially hippocampal GABA in the pathophysiology underlying psychiatric conditions accompanied by intrusive thoughts. Importantly, this insight was made possible, in part, by clinical work with animal models.
CNS: Is there anything else you’d like to add?
Schmitz: We are our brains. If our neurotransmitters are severely altered, for example by disease, this will influence our cognitive capacities and our behaviors, which define who we are.
-Lisa M.P. Munoz
