Discussion: Short-Term Memory-Related LFP Oscillation in the Prefrontal Cortex

(two-sample) UE analysis of the activity of these 27 cells, we have found JS activity that was performance-related and indicated by stronger synchronization if the monkey performed the task correctly. The tight linking of these performance-related modulations of the synchronization to the monkey’s task indicates that neuronal assemblies are formed task-related and are necessary for the monkey to classify successfully the stimuli as match or non-match.

In a third step (see Section 9.4), we tested, based on the same 27 single-units, to which degree neuronal assemblies are related to the motor actions of the monkey (see Section 9.4). During the first period of the test presentation (150 to 550 ms after test onset), modulations in the number of JS patterns of complexities 2 and 5, with significant modulations of the normalized synchrony, seem to be performance-related rather than motor-performance-related. After this first period, during which the maintained stimulus from the sample has to be compared to the test-stimulus to allow for a correct response by the monkey, the modulations in the number of JS patterns with significant modulations of the normalized synchrony become motor-related. This motivates the hypothesis that activity in the prefrontal cortex is related to decision making rather than to stimulus maintenance.

To validate these findings we have dithered spikes in the original dataset with±6 ms (see Section 9.5).

After applying the dithering to the spikes, the total number of JS patterns that expressed significant modulations of the normalized synchrony went down to 20% for complexity 2, 12% for complexity 3, 5%

for complexity 4, 2% for complexity 5, and 0.3% for complexity 6. That means in case of complexity 6 JS patterns that 99.7% of the JS patterns, which had significant modulations of the normalized synchrony before dithering, became non-modulated after dithering. This finding strongly indicates that, indeed, the fine-temporal cross-structure on a time scale of less than 12 ms has caused the above reported effects and results.

Despite these results, since we used only one experiment, we cannot generalize these latter findings so far. Nevertheless, the robustness and the strength of the observed modulations motivate the hypothesis that the formation of neuronal assemblies and the strengthening or weakening of synchronization across large groups of neurons is correlated to the periods of sample presentation, early and late delay, the test stimulus presentation, and the motor action, as well as correlated to the monkey’s performance.

10.3. Discussion: Short-Term Memory-Related LFP Oscillation in the Prefrontal Cortex

In this study, we investigated first, whether task-related oscillations occur in local field potentials (LFPs) of ventral prefrontal cortex of an awake monkey performing an STM task and second, whether power and phase-locking of oscillations in various frequency bands is correlated with behavioral performance and identifies the presented stimuli (see Chapter 8). To this end, we applied the bi-variate and multi-variate

bootstrapping tool that has been developed during this thesis (Section 4.1.4 and Chapter 5) to analyze the data. We geared the developed tools to test 3 working hypotheses:

Working hypothesis 1: Neuronal oscillations and their synchronization are involved in processes underlying the STM in the pre-frontal cortex.

Working hypothesis 2: Oscillation of and coupling across neuronal cell assemblies are modulated in their amplitude and strength by the task and behavior of the monkey.

Working hypothesis 3: Oscillation of neuronal cell assemblies is carrying information about the memoranda and, therefore, is likely to be involved in the maintenance of information.

10.3.1. Oscillations and Synchronization Involved in Short-Term Memory

Given typical electrophysiological recordings, we were concerned about two frequent observations. First, properties or statistics that are used to describe the data might have large variabilities, and second, the experimental conditions or the state of the investigated system might change during the experiment, since the latter can last anywhere between a couple of minutes to a couple of hours. These changes can either be induced by manipulations from outside (e.g. changed level of anaesthesia, drugs, etc.) or might be intrinsic, caused by changes in the experimental animal. In an awake animal, such as the awake monkeys from whom we have analyzed data, these intrinsic changes might occur due to different levels of alertness, tiredness or motivation. In addition episodical changes without any obvious reason might occur. We developed tools that account for these changes and that enabled us first, to perform bi-variate and multi-variate testing of the power and phase-locking in the case of two orN conditions, respectively, and second, to test if detected effects were significant, stable and reliable across the experiment (Section 4.1.4 and Chapter 5).

To test our three working hypotheses, we performed four analyses. First, we studied the precision and spatial extent of synchronization among recording sites, by assessing phase-locking and its performance-related modulations. Second, we identified performance-dependent modulations (bi-variate design) of the oscillation amplitude and the phase-locking. Third, we performed, in analogy with the bivariate test, a multi-variate test to identify stimulus-specific oscillations. Fourth, we compared and distinguished between performance- and stimulus-related power changes to allow for a mechanistic model of processes that are underlying the STM.

10.3.2. Spatial Extend of Neuronal Oscillation and Synchronization

We studied the precision and spatial extent of synchronization among recording sites by assessing phase-locking and its performance-related modulations (see Section 8.3.7). The results indicate that neuronal

10.3. Discussion: Short-Term Memory-Related LFP Oscillation in the Prefrontal Cortex

oscillations in the beta and low-gamma bands between 10 Hz and 45 Hz are synchronized over a larger spatial extent than the average electrode spacing (400-900µm), while neuronal oscillations above 50 Hz were not synchronized. This suggests that faster oscillations are restricted to single, or at most a few, cortical columns (Pucak et al., 1996) while slower oscillations involve many columns and probably other cortical areas. This is supported by studies showing that beta- but not gamma-oscillations synchronize across remote cortical areas (Brovelli et al., 2004; Roelfsema et al., 1997).

10.3.3. Performance-Related and Memorandum-Specific Neuronal Oscillation

Low-gamma components (30-45 Hz), which occurred during the early and late parts of the delay period, were both related and stimulus-selective, while beta components were only performance-related (see Section 8.3.5). In analogy with the mechanistic idea that information is maintaind by sustained activation similar to a labeled line code (Durstewitz et al., 2000; Fuster and Alexander, 1971;

Goldman-Rakic, 1995; Gutkin et al., 2001; Miller et al., 1993), we were interested in signal modulations that lasted throughout the entire delay period. We found that among the memory-related signals, only the performance- and stimulus-related increases of oscillations in the high-gamma-band (65-90 Hz) lasted throughout the entire memory delay.

Because these high-frequency oscillations exhibited also stimulus-selectivity, the sustained modulations of high-frequency gamma-oscillations might constitute an important part of the maintenance process (see Section 8.4). Nevertheless, the mechanistic idea that information is maintained by sustained activity and, therefore, bound to localized units might be an over-simplification. Rather, information may be maintained through the trajectories of changing network activity that are an identical representation of the memorandum (Maass et al., 2002; Maass et al., 2004). The latter implies, first, that not the states themselves, but rather the trajectories are maintaining the information and second, that states that maintain information do not have to be sustained or stable in time.

Our measurements based onλ-maps account for this, sinceλ-maps represent the percentage of sites or pairs that expressed performance- or stimulus-related modulations (see Section 8.3.3). Therefore, it is not required that modulations ofλbe due to the same sites and pairs throughout the whole delay. Indeed, our results of individual sites or pairs indicate that the performance- and stimulus-related increases of oscillations in the high gamma band, which lasted throughout the entire memory, are based on groups of sites and pairs that change over time.

Thus, we found evidence that the information about the memorized stimuli must be distributed across a large number of such local oscillating networks. Otherwise our arbitrary sampling of a few sites from a small patch of cortex would not have yielded that many sites with memory-related activity. Also, we found that units that are involved in the maintenance of information are changing during the delay.

The low average phase-locking (<0.2) of these high-gamma oscillations (>50 Hz) implies that the

spa-tial extent of the processes based on high-frequency oscillations was small (see Section 8.3.7). This raises the question of how local processes that maintain information can be integrated into a larger network.

The high phase-locking (>0.5) of beta- and low-gamma oscillations across the extension of the electrode-grid, its persistence throughout the entire trial duration, and the performance-dependence of this locking suggest that slower oscillations might provide a global temporal reference signal for the coordination of the distributed local processes, which contain information about the stimuli. The transient episodes of beta- and low-gamma oscillations occurring at the beginning and the end of the maintenance interval were performance-dependent, but only the gamma- and not the beta-oscillations were stimulus-selective during these epochs. This might suggest that the transient beta/low-gamma oscillations serve the organi-zation of the memory process during transitions from encoding to maintenance and from maintenance to retrieval. Alternatively, these episodes with beta/low-gamma oscillations could directly reflect encoding and retrieval processes. We prefer the first interpretation, because these low-frequency oscillations were not stimulus-selective.

A more likely correlate of encoding and retrieval processes are the high-gamma oscillations, because they had shorter latencies and were stimulus-selective. As suggested by strong phase-locking of low-frequency oscillations across the whole electrode grid, these oscillations appear to comprise larger networks. Be-cause these persist during the maintenance interval, while stimulus-selective oscillations decrease their frequency in mid delay, these slower oscillations could reflect a rehearsal or recruitment process that involves representations in other cortical areas, such as visual area V4, for which locking of spikes to slow oscillations has been shown to occur during STM (Lee et al., 2005).

10.3.4. Model of Processes Underlying Short-Term Memory

We compared performance-related with stimulus-selective time frequency zones and identified overlaps between both. These overlaps could reflect interactions of different sub-processes that need to be coordi-nated during the memory process (see Section 8.5). In particular, during early delay, two transient zones around 20 Hz and 40 Hz coincided with a sustained time-frequency-zone (’TF-zone’) around 80 Hz, all re-flecting increases of power in correct trials. Since power around 60 Hz was not modulated, the interaction of the 20 Hz and 80 Hz processes could be mediated by a 40 Hz process, as a harmonic of the 20 Hz and a sub-harmonic of the 80 Hz process. This suggests that the 40 Hz process could mediate a handshake between a global performance-dependent 20 Hz and a local stimulus-selective 80 Hz process by means of a 1:2 and 2:1 synchronization (see Section 3.3 ). Such a synchronization among harmonic frequencies was recently reported for human MEG (Palva et al., 2005). During the proposed period of handshaking, the bandwidth of the local high-frequency processes is sharpened in relation to the pre-sample and sample periods. Therefore, it is conceivable that the power increase of the global and performance-dependent 20 Hz and 40 Hz oscillations serve to tune and coordinate the local stimulus-selective high-frequency