THE HOMOGENOUS HIPPOCAMPUS: HOW HIPPOCAMPAL CELLS PROCESS AVAILABLE AND POTENTIAL GOALS.

We present here a view of the firing patterns of hippocampal cells that is contrary, both functionally and anatomically, to conventional wisdom. We argue that the hippocampus responds to efference copies of goals encoded elsewhere; and that it uses these to detect and resolve conflict or interference between goals in general. While goals can involve space, hippocampal cells do not encode spatial (or other special types of) memory, as such. We also argue that the transverse circuits of the hippocampus operate in an essentially homogeneous way along its length. The apparently different functions of different parts (e.g. memory retrieval versus anxiety) result from the different (situational/motivational) inputs on which those parts perform the same fundamental computational operations. On this view, the key role of the hippocampus is the iterative adjustment, via Papez-like circuits, of synaptic weights in cell assemblies elsewhere.

Midfrontal theta reactivity to conflict and error are linked to externalizing and internalizing respectively.

Dimensional psychopathology scores measure symptom severity; cutting across disorder categories. Their clinical utility is high given comorbidity, but their neural basis is unclear. We used scalp electroencephalography (EEG) to concurrently assess neural activity across internalizing and externalizing traits. "Theta rhythm" (4-7 Hz) spectral power at the frontal midline site Fz in specific goal conflict and action error phases within a trial of a Stop-Signal Task was extracted using process-specific contrasts. A final sample of 146 community participants (63 males, 83 females; mean age = 36; SD = 9; range = 18 - 56), oversampled for externalizing disorder (49% diagnosed with a DSM-5 externalizing disorder), also supplied psychopathology and personality data. We used the Minnesota Multiphasic Personality Inventory-3 (MMPI-3) to measure symptoms and traits of psychopathology. An MMPI-3 measure of the higher-order internalizing psychopathology spectrum was positively correlated with action error theta. An MMPI-3 measure of the higher-order spectrum of externalizing psychopathology was negatively correlated with goal-conflict theta. We showed that goal-conflict and error theta activity are higher-order processes that index psychopathology severity. The associations extend into the nominally healthy range, and so reflect theta-related factors that apply to the general population as well as patients with sub-threshold diagnoses.

Midfrontal conflict theta and parietal P300 are linked to a latent factor of DSM externalising disorders.

Psychiatric illnesses form spectra rather than categories, with symptoms varying continuously across individuals, i.e., there is no clear break between health and disorder. Dimensional measures of behaviour and brain activity are promising targets for studying biological mechanisms that are common across disorders. Here, we assessed the extent to which neural measures of the sensitivity of the three biological systems in the reinforcement sensitivity theory (RST) could account for individual differences in a latent general factor estimated from symptom counts across externalising disorders (EXTs). RST explanatory power was pitted against reduced P300, a reliable indicator of externalising per previous research. We assessed 206 participants for DSM-5 EXTs (antisocial personality disorder, conduct disorder, attention-deficit/hyperactivity disorder, intermittent explosive disorder symptoms, alcohol use disorder, and cannabis use disorder). Of the final sample, 49% met diagnostic criteria for at least one of the EXTs. Electroencephalographic measures of the sensitivities of the behavioural activation system (BAS), the fight/flight/freeze system, and the behavioural inhibition system (BIS), as well as P300 were extracted from the gold bar-lemon and stop-signal tasks. As predicted, we found that low neural BIS sensitivity and low P300 were uniquely and negatively associated with our latent factor of externalising. Contrary to prediction, neural BAS/"dopamine" sensitivity was not associated with externalising. Our results provide empirical support for low BIS sensitivity and P300 as neural mechanisms common to disorders within the externalising spectrum; but, given the low N involved, future studies should seek to assess the replicability of our findings and, in particular, the differential involvement of the three RST systems.

Examination of associations between psychopathy and neural reinforcement sensitivity theory constructs.

We investigated psychopathy from the neurobiological perspective of reinforcement sensitivity theory (RST). In contrast to previous semantically derived self-report scales, we operationalised RST systems neurally with evoked electroencephalography (EEG). Participants were from a community sample weighted towards externalising psychopathology. We compared the Carver & White Behavioural Inhibition System (BIS)/Behavioural Approach System (BAS) scales with EEG responses associated with RST's systems of goal conflict (aka 'behavioural inhibition'), repulsion/outcome conflict (aka 'fight/flight/freeze') and attraction (aka 'approach'). Bivariate correlations and multiple regression analysis yielded results generally consistent with past literature for associations between psychopathy and the self-report BIS/BAS scales. There were some differences from self-report associations with neural measures of RST. With EEG measures, (1) no meaningful associations were observed between any psychopathy scales and the attraction system; (2) affective-interpersonal traits of psychopathy were negatively associated with goal conflict; (3) disinhibition-behavioural traits of psychopathy were negatively associated with goal conflict but, unexpectedly, positively associated with outcome conflict. These results indicate frontal-temporal-limbic circuit dysfunction in psychopathy as specific domains were linked to neural deficits in goal conflict processing, but there was no evidence for deficits in attraction-related processes.

Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study.

BACKGROUND: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). AIMS: To evaluate mood rating, safety and tolerability data from patients with TRD treated with ketamine and the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated with mood response. METHODS: We evaluated the efficacy and safety of intramuscular racemic ketamine in 25 patients with TRD, using a double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 and 1 mg/kg, and the psychoactive control was fentanyl 50 mcg, given at weekly intervals. RESULTS/OUTCOMES: Within 1 h of ketamine dosing, patients reported reduced depression and anxiety ratings, which persisted for up to 7 days. A dose-response profile for ketamine was noted for dissociative side effects, adverse events and changes in blood pressure; however, changes in mood ratings were broadly similar for both ketamine doses. Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression Scale (HADS), and 18/25 (72%) were responders for the HADS-anxiety scale. After fentanyl, only 1/25 (HADS-depression) and 3/25 (HADS-anxiety) were responders. Ketamine was generally safe and well tolerated in this population. CONCLUSIONS: Our findings add to the literature confirming ketamine's activity against depressive and anxiety symptoms in patients with TRD.

Non-human contributions to personality neuroscience - from fish through primates. An introduction to the special issue.

The most fundamental emotional systems that show trait control are evolutionarily old and extensively conserved. Psychology in general has benefited from non-human neuroscience and from the analytical simplicity of behaviour in those with simpler nervous systems. It has been argued that integration between personality, psychopathology, and neuroscience is particularly promising if we are to understand the neurobiology of human experience. Here, we provide some general arguments for a non-human approach being at least as productive in relation to personality, psychopathology, and their interface. Some early personality theories were directly linked to psychopathology (e.g., Eysenck, Panksepp, and Cloninger). They shared a common interest in brain systems that naturally led to the use of non-human data; behavioural, neural, and pharmacological. In Eysenck's case, this also led to the selective breeding, at the Maudsley Institute, of emotionally reactive and non-reactive strains of rat as models of trait neuroticism or trait emotionality. Dimensional personality research and categorical approaches to clinical disorder then drifted apart from each other, from neuropsychology, and from non-human data. Recently, the conceptualizations of both healthy personality and psychopathology have moved towards a common hierarchical trait perspective. Indeed, the proposed two sets of trait dimensions appear similar and may even be eventually the same. We provide, here, an introduction to this special issue of Personality Neuroscience, where the authors provide overviews of detailed areas where non-human data inform human personality and its psychopathology or provide explicit models for translation to human neuroscience. Once all the papers in the issue have appeared, we will also provide a concluding summary of them.

Prefrontal and hippocampal theta rhythm show anxiolytic-like changes during periaqueductal-elicited "panic" in rats.

Anxiety and panic are both elicited by threat and co-occur clinically. But, at the neural level, anxiety appears to inhibit the generation of panic; and vice versa. Anxiety and panic are thought to engage more anterior (a) and mid-posterior (m) parts of the periaqueductal gray (PAG), respectively. Anxiety also engages the hippocampus and medial prefrontal cortex. Here, we tested if mPAG but not aPAG stimulation would suppress prefrontal and hippocampal theta rhythm as do anxiolytic drugs. Twelve male rats with implanted electrodes were stimulated alternately (30 s interval) in the left PAG or right reticular formation (reticularis pontis oralis [RPO]-as a positive control) with recording in the left prelimbic cortex and left and right hippocampus. PAG stimulation was set to produce freezing and RPO to produce 7-8 Hz theta rhythm before tests lasting 10 min on each of 5 days. mPAG stimulation decreased, and aPAG increased, theta power at all sites during elicited freezing. mPAG, but not aPAG, stimulation decreased prefrontal theta frequency. Stimulation did not substantially change circuit dynamics (pairwise phase consistency and partial directed coherence). Together with previous reports, our data suggest that panic- and anxiety-control systems are mutually inhibitory, and neural separation of anxiety and panic extends down to the aPAG and mPAG, respectively. Our findings are consistent with recent proposals that fear and anxiety are controlled by parallel neural hierarchies extending from PAG to the prefrontal cortex.

Right Frontal Theta: Is It a Response Biomarker for Ketamine's Therapeutic Action in Anxiety Disorders?

Anxiety disorders are the most prevalent mental disorders in the world, creating huge economic burdens on health systems and impairing the quality of life for those affected. Recently, ketamine has emerged as an effective anxiolytic even in cases resistant to conventional treatments (TR); but its therapeutic mechanism is unknown. Previous data suggest that ketamine anxiety therapy is mediated by reduced right frontal electroencephalogram (EEG) theta power measured during relaxation. Here we test for a similar theta reduction between population-sample, presumed treatment-sensitive, (TS) anxiety patients and healthy controls. Patients with TS DSM-5 anxiety disorder and healthy controls provided EEG during 10 min of relaxation and completed anxiety-related questionnaires. Frontal delta, theta, alpha1, alpha2, beta, and gamma power, Higuchi's fractal dimension (HFD) and frontal alpha asymmetry (FAA) values were extracted to match ketamine testing; and we predicted that the controls would have less theta power at F4, relative to the TS anxious patients, and no differences in HFD or FAA. We provide graphical comparisons of our frontal band power patient-control differences with previously published post-pre ketamine TR differences. As predicted, theta power at F4 was significantly lower in controls than patients and FAA was not significantly different. However, HFD was unexpectedly reduced at lateral sites. Gamma power did not increase between controls and patients suggesting that the increased gamma produced by ketamine relates to dissociation rather than therapy. Although preliminary, and indirect, our results suggest that the anxiolytic action of ketamine is mediated through reduced right frontal theta power.

Dynamic interaction between hippocampus, orbitofrontal cortex, and subthalamic nucleus during goal conflict in the stop signal task in rats.

Action stopping depends on at least two (fast, slow) frontal circuits depending on the urgency of execution of the 'go' response. Human EEG suggests a third (even slower, limbic) circuit that activates frontal areas at frequencies typical of 'hippocampal theta'. Here we test in male rats whether stop-go conflict engages the hippocampus and so may send theta-modulated information via the frontal cortex to the subthalamic nucleus. We recorded from multi-electrode arrays in the hippocampus, orbitofrontal cortex, and subthalamus in 5 male Long Evans rats performing a stop signal task and, as in previous human experiments, assessed stop-signal specific power for effects of goal conflict. Conflict increased 11-12 Hz theta power modestly in all three structures but with the largest increase in power being at 5 Hz in the frontal cortex but not the hippocampus. There was increased conflict-related coherence in all circuits in the range 5-8 Hz and particularly at 5-6 Hz. Increased coherence coupled with an increase in conflict-induced low frequency power in the frontal cortex may reflect communication with the hippocampus. The data are consistent with a third limbic circuit that can generate stopping when go responses are particularly slow (as, e.g., in a go/no go task). [199 words; 200 max].

Construction of complex memories via parallel distributed cortical-subcortical iterative integration.

The construction of complex engrams requires hippocampal-cortical interactions. These include both direct interactions and ones via often-overlooked subcortical loops. Here, we review the anatomical organization of a hierarchy of parallel 'Papez' loops through the hypothalamus that are homologous in mammals from rats to humans. These hypothalamic loops supplement direct hippocampal-cortical connections with iterative reprocessing paced by theta rhythmicity. We couple existing anatomy and lesion data with theory to propose that recirculation in these loops progressively enhances desired connections, while reducing interference from competing external goals and internal associations. This increases the signal-to-noise ratio in the distributed engrams (neocortical and cerebellar) necessary for complex learning and memory. The hypothalamic nodes provide key motivational input for engram enhancement during consolidation.

Early and late signals of unexpected reward contribute to low extraversion and high disinhibition, respectively.

Like socio-economic status and cognitive abilities, personality traits predict important life outcomes. Traits that reflect unusually low or high approach motivations, such as low extraversion and high disinhibition, are linked to various forms of mental disorder. Similarly, the dopamine system is theoretically linked to approach motivation traits and to various forms of mental disorder. Identifying neural contributions to extremes of such traits should map to neural sources of psychopathology, with dopamine a prime candidate. Notably, dopamine cells fire in response to unexpected reward, which suggests that the size of non-invasive, scalp-recorded potentials evoked by unexpected reward could reflect sensitivity in approach motivation traits. Here, we evaluated the validity of evoked electroencephalography (EEG) responses to unexpected reward in a monetary gain/loss task to assess approach motivation traits in 137 participants, oversampled for externalizing psychopathology symptoms. We demonstrated that over the 0-400 ms period in which feedback on the outcome was presented, responses evoked by unexpected reward contributed to all theoretically relevant approach motivation trait domains (disinhibition, extraversion and the behavioural activation system); and did so only at times when dopamine responses normally peak and reportedly code salience (70-100 ms) and valuation (200-300 ms). In particular, we linked "dopaminergic" salience and valuation to the psychopathology-related constructs of low extraversion (social anxiety) and high disinhibition (impulsivity) respectively, making the evoked potential components biomarker candidates for indexing aberrant processing of unexpected reward.

Right frontal anxiolytic-sensitive EEG 'theta' rhythm in the stop-signal task is a theory-based anxiety disorder biomarker.

Psychiatric diagnoses currently rely on a patient's presenting symptoms or signs, lacking much-needed theory-based biomarkers. Our neuropsychological theory of anxiety, recently supported by human imaging, is founded on a longstanding, reliable, rodent 'theta' brain rhythm model of human clinical anxiolytic drug action. We have now developed a human scalp EEG homolog-goal-conflict-specific rhythmicity (GCSR), i.e., EEG rhythmicity specific to a balanced conflict between goals (e.g., approach-avoidance). Critically, GCSR is consistently reduced by different classes of anxiolytic drug and correlates with clinically-relevant trait anxiety scores (STAI-T). Here we show elevated GCSR in student volunteers divided, after testing, on their STAI-T scores into low, medium, and high (typical of clinical anxiety) groups. We then tested anxiety disorder patients (meeting diagnostic criteria) and similar controls recruited separately from the community. The patient group had higher average GCSR than their controls-with a mixture of high and low GCSR that varied with, but cut across, conventional disorder diagnosis. Consequently, GCSR scores should provide the first theoretically-based biomarker that could help diagnose, and so redefine, a psychiatric disorder.

Laterality of an EEG anxiety disorder biomarker largely follows handedness.

Anxiety disorders are the most common mental disorders impacting people worldwide. Using an auditory Stop Signal Task (SST), we have developed an anxiety disorder biomarker (goal-conflict specific rhythmicity/GCSR) that occurs at the right frontal site F8 in right-handed participants. Here, we compare its laterality in left-handers (n = 26) versus demographically-matched right-handers (n = 26) between the ages of 18-30. We assessed the effects on GCSR power of the handedness of the participants (left or right), blocks of the SST, left-right variation across frontal channels (F7, F3, Fz, F4, F8), and EEG frequency (4-12 Hz). Left-handers differed from right-handers most at the channels furthest from the midline. This difference was largely a mirroring of right hander responses by left handers. With frontal channels coded in reverse order for left handers the original significant differences disappeared. Some differences remained between the groups in the frequency variation across blocks of testing. These and other data suggest that the circuitry engaged by conflict in the SST is different from that directly controlling stopping behaviour. Our results also suggest that where GCSR is used as an anxiety process or disorder biomarker in groups that combine both left and right-handed people, data only from the channel ipsilateral to the dominant hand should be used (F7, or F8, respectively).

Construction of simple, customised, brain-spanning, multi-channel, linear microelectrode arrays.

BACKGROUND: The construction of multichannel micro-electrode arrays (MEA) generally requires complex and expensive procedures. Here we describe a simple, cheap, flexible method of linear MEA construction. NEW METHOD: Our method allows manufacture of linear MEA (cross section ∼ 375 × 250 µm with 12 electrodes) of any desired length, with customized spacing of the electrode tips (down to a minimum spacing of 200 µm or less) to suit different needs and experiments. We describe the following steps: (1) set-up for MEA construction; (2) building of a construction jig; (3) building the reference, ground and optional electrical stimulation electrodes; (4) treatment of the main recording microwires; (5) soldering of the microwires to the main connector plug and arrangement of the microwires in a customizable array; and (6) testing of the MEA resistance and correct connections. Finally, we describe methods for quick surgical implantation of multiple MEAs and bipolar micro-stimulation electrodes for in vivo experiments in free-moving rats. RESULTS: We provide examples of multi-site local field potentials from prolonged recordings in awake and free-moving rodents, with recordings viable for months, as well as samples of electrical stimulation effects on cortical and hippocampal recordings. Hippocampal recordings showed clear phase reversal and amplitude changes across its layers. CONCLUSIONS: We briefly discuss how the arrays can support other forms of stimulation such as optogenetic probes.

Speed modulation of hippocampal theta frequency and amplitude predicts water maze learning.

Theta oscillations in the hippocampus have many behavioral correlates, with the magnitude and vigor of ongoing movement being the most salient. Many consider correlates of locomotion with hippocampal theta to be a confound in delineating theta contributions to cognitive processes. Theory and empirical experiments suggest theta-movement relationships are important if spatial navigation is to support higher cognitive processes. In the current study, we tested if variations in speed modulation of hippocampal theta can predict spatial learning rates in the water maze. Using multi-step regression, we find that the magnitude and robustness of hippocampal theta frequency versus speed scaling can predict water maze learning rates. Using a generalized linear model, we also demonstrate that speed and water maze learning are the best predictors of hippocampal theta frequency and amplitude. Our findings suggest movement-speed correlations with hippocampal theta frequency may be actively used in spatial learning.

Personality neuroscience and psychopathology: should we start with biology and look for neural-level factors?

"Personality is an abstraction used to explain consistency and coherency in an individual's pattern of affects, cognitions, desires and behaviors [ABCDs]" (Revelle, 2007, p. 37). But personality research currently provides more a taxonomy of patterns than theories of fundamental causes. Psychiatric disorders can be viewed as involving extremes of personality but are diagnosed via symptom patterns not biological causes. Such surface-level taxonomic description is necessary for science, but consistent predictive explanation requires causal theory. Personality constructs, and especially their clinical extremes, should predict variation in ABCD patterns, with parsimony requiring the lowest effective causal level of explanation. But, even biologically inspired personality theories currently use an intuitive language-based approach for scale development that lacks biological anchors. I argue that teleonomic "purpose" explains the organisation and outputs of conserved brain emotion systems, where high activation is adaptive in specific situations but is otherwise maladaptive. Simple modulators of whole-system sensitivity evolved because the requisite adaptive level can vary across people and time. Sensitivity to a modulator is an abstract predictive personality factor that operates at the neural level but provides a causal explanation of both coherence and occasional apparent incoherence in ABCD variation. Neuromodulators impact all levels of the "personality hierarchy" from metatraits to aspects: stability appears altered by serotonergic drugs, neuroticism by ketamine and trait anxiety by simple anxiolytic drugs. Here, the tools of psychiatry transfer to personality research and imply both interaction between levels and oblique factor mappings to ABCD. On this view, much psychopathology reflects extremes of neural-level personality factors, and we can view much pharmacotherapy as temporarily altering personality. So, particularly for personality factors linked to basic emotions and their disorders, I think we should start with evolutionary biology and look directly at conserved neural-level modulators for our explanatory personality constructs and only invoke higher order, emergent, explanations when neural-level explanation fails.

Goal-Conflict EEG Theta and Biased Economic Decisions: A Role for a Second Negative Motivation System.

Economic decision biases can reflect emotion and emotion dysfunction. Economic paradigms thus provide a solid framework for analysis of brain processes related to emotion and its disorders. Importantly for economic decisions, goal-conflict activates different negative motivational processes than pure loss; generating negative decision biases linked to anxiety and fear, respectively. Previously, right frontal goal-conflict specific EEG rhythmicity (GCSR) was shown to reflect anxiety processing. Here, we assessed GCSR in a forced-choice, economic decision-making task. Ninety participants were tested in three key conditions where gain:loss ratios of left mouse clicks were set to 75:25 (GAIN), 50:50 (CONFLICT) and 25:75 (LOSS). Right clicks produced no monetary consequences and skipped the current trial. The participants were not told the different conditions but could learn about them by associating the background stimulus color with the specific payoff. Goal-conflict was defined as the mathematical contrast of activity in CONFLICT minus the average of that in GAIN and LOSS. Replicating previous findings with somewhat different conditions, right frontal GCSR was detected. Importantly, greater right frontal GCSR significantly predicted a preference for economic safety in CONFLICT but not in GAIN or LOSS; but did not predict trait anxiety or neuroticism. We conclude that goal-conflict has unique neuroeconomics effects on choice biases; and that these reflect anxiety processing that is not effectively captured by trait anxiety or neuroticism.

Mixed Effects of Low-dose Ethanol on Cortical and Hippocampal Theta Oscillations.

Ethanol is one of the most widely used drugs - with many psychoactive effects, including anxiolysis. The deleterious effects on brain function and general health of chronic and high-level ethanol use are well-studied. However, the neurophysiology of acute low dose ethanol has not been systematically investigated. Here, we examined the effects of low dose (0.25 and 0.5 g/kg) ethanol on midline (prefrontal, cingulate and retrosplenial) neocortical and hippocampal theta oscillations in freely moving rats. We also tested low dose ethanol on reticular-elicited and running-elicited hippocampal theta frequency and assessed the linear relationship of theta frequency to stimulation intensity and running speed, respectively. Low dose ethanol had mixed effects on neocortical theta oscillations. It most reliably reduced theta frequency, produced a weak inverted-U effect on theta power, and had no detectable effect on cortico-hippocampal theta coherence. Ethanol dose-dependently decreased the y-intercept of the speed-theta frequency function without affecting the slope, but decreased the slope of the stimulation intensity-theta frequency function without affecting the y-intercept; thus decreasing theta frequency in both cases. We conclude low dose ethanol has weak but detectable effects on neocortical and hippocampal theta oscillations. These effects may underlie positive cognitive and behavioural outcomes reported in the literature using low dose ethanol. The double dissociation of slope and y-intercept specific changes relating to different methods of hippocampal theta elicitation presents the potential to probe multiple mechanisms contributing to anxiolytic effects on theta and so hippocampal function.